Cdk2 inhibitors and methods of using the same

Abstract

The present disclosure provides compounds, compositions thereof, and methods of using the same for the inhibition of CDK2, and the treatment of CDK2 related diseases and disorders.

Description

CDK2 INHIBITORS AND METHODS OF USING THE SAMECROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority to U.S. Provisional Application No. 63 / 393,066, filed July 28, 2022, the entire contents of which is herein incorporated by reference.FIELD

[0002] The present disclosure relates generally to Cyclin-dependent kinase 2 (CDK2) inhibiting chemical compounds and uses thereof in the inhibition of the activity of CDK2. The disclosure also provides pharmaceutically acceptable compositions comprising compounds disclosed herein and methods of using said compounds and compositions in the treatment of various disorders related to CDK2 activity.BACKGROUND

[0003] Cell cycle dysregulation, including uncontrolled cell growth, impaired cell differentiation and abnormal apoptosis have been shown to be caused by over activity of Cyclin-dependent kinases (CDKs). CDKs are important serine / threonine protein kinases that become active when combined with a specific cyclin partner. There are various subtypes of CDKs, each having a different role during the cell cycle, with varying levels of activity during each of the phases. CDK1, CDK2, CDK4 and CDK6 have been found to be specifically important subtypes, where over activity of one or more of these subtypes may lead to dysregulation of the cell cycle and the development of a variety of cancers. The S phase of the cell cycle is responsible for DNA replication and is the phase where aberrant DNA replication may occur. The CDK2 / cyclin E complex is required for the cell cycle transition from the G1 phase to the S phase and the CDK2 / cyclin A complex is required for the cell cycle transition from the S phase to the G2 phase. Therefore, selective inhibition of the CDK2 / cyclin E and / or CDK2 / cyclin A complexes can prevent aberrant DNA replication and can be used to treat certain cancers.

[0004] Accordingly, there is a need for the development of compounds capable of inhibiting the activity of CDK2 / cyclin complexes, and pharmaceutical compositions thereof, for the prevention, and treatment of CDK2 related diseases or disorders.SUMMARY

[0005] The present disclosure is based at least in part on the identification of compounds that bind and inhibit Cyclin-dependent kinase 2 (CDK2) and / or CDK2 / cyclin complexes and methods ofusing the same to treat diseases associated with CDK2 activity. Disclosed herein is a compound according to Formula IA or a pharmaceutically acceptable salt thereof:wherein each variable is as defined and described herein.

[0006] Compounds of the present disclosure, and pharmaceutically acceptable compositions thereof, are useful for treating a variety of diseases, disorders or conditions, associated with CDK2 activity. Such diseases, disorders, or conditions include those described herein. DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS 1. General Description of Compounds of the Disclosure:

[0007] The present disclosure provides compounds capable of inhibiting Cyclin-dependent kinase 2 (CDK2) and / or CDK2 / cyclin complexes.

[0008] In some embodiments, the inhibitors of CDK2 include compounds of Formula IA:or a pharmaceutically acceptable salt thereof, wherein: RAisRBis hydrogen, an optionally substituted C1-6aliphatic group, -OR, -NR2or a halogen; L1is a covalent bond or a saturated or unsaturated, straight or branched, optionally substituted bivalent C1-6hydrocarbon chain, wherein 0-2 methylene units of L1are independently replaced by -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -C(S)-, -NRS(O)2-, - S(O)2NR-, -NRC(O)-, -C(O)NR-, -OC(O)NR-, -NRC(O)O-, or -NRC(O)NR-; R1is hydrogen, an optionally substituted C1-6aliphatic group, or an optionally substituted cyclic group selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring that is optionally bridged bicyclic or spirocyclic (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and an 8-10 membered bicyclic heteroaromatic ring (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur); R2is hydrogen, an optionally substituted C1-6aliphatic group, –C1-6alkylene-OR,–C1-3alkylene-O-C1-3alkylene-R,–C(O)OR, –C(O)NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -P(O)R2, – C(O)NRS(O)2R, or an optionally substituted cyclic group selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and an 8-10 membered bicyclic heteroaromatic ring (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur); and R3is hydrogen; or R2and R3together with the intervening carbon atom form an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring, or an optionally substituted 3-7membered saturated or partially unsaturated heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur); R4is an optionally substituted cyclic group selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and an 8-10 membered bicyclic heteroaromatic ring (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur); and R5is hydrogen; or R4and R5together with the intervening nitrogen atom form an optionally substituted 4-7 membered saturated, or partially unsaturated heterocyclic ring (having 0-2 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur), or an optionally substituted heteroaryl ring (having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur); L2is a saturated or unsaturated, straight or branched, optionally substituted bivalent C1-4hydrocarbon chain, wherein 0-2 methylene units of L2are independently replaced by -O-, -NR-, - S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -C(S)-, -NRS(O)2-, -S(O)2NR-, -NRC(O)-, - C(O)NR-, -OC(O)NR-, -NRC(O)O-, or -NRC(O)NR-; R6is an optionally substituted C1-6aliphatic group, or a cyclic group selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and an 8-10 membered bicyclic heteroaromatic ring (having 1-5 heteroatomsindependently selected from nitrogen, oxygen, and sulfur), wherein the cyclic group is optionally substituted with one or more instances of R7; each instance of R7is independently halogen, –CN, –NO2, –OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, –C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, –N(R)S(O)2R, an optionally substituted C1-6aliphatic group, an optionally substituted C1-6aliphatic-Cy group, or Cy; L3is a saturated or unsaturated, straight or branched, optionally substituted bivalent C1-4hydrocarbon chain, wherein 0-2 methylene units of L3are independently replaced by -O-, -NR-, - S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -C(S)-, -NRS(O)2-, -S(O)2NR-, -NRC(O)-, - C(O)NR-, -OC(O)NR-, -NRC(O)O-, or -NRC(O)NR-; R8is a cyclic group selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and an 8-10 membered bicyclic heteroaromatic ring (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the cyclic group is optionally substituted with one or more instances of R9; each instance of R9is independently halogen, –CN, –NO2, –OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, –C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, –N(R)S(O)2R, an optionally substituted C1-6aliphatic group, an optionally substituted C1-6aliphatic-Cy group, or Cy; each Cy is independently an optionally substituted cyclic group selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatomsindependently selected from nitrogen, oxygen, and sulfur), a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and a 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); and each R is independently hydrogen, or an optionally substituted C1-6aliphatic group, an optionally substituted phenyl, an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring, an optionally substituted 3-7 membered saturated or partially unsaturated heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), or an optionally substituted 5-6 membered heteroaryl ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); or when there are two R groups on the same nitrogen they are taken together with their intervening atoms to form a cyclic group selected from a 4-7 membered saturated, partially unsaturated, or heteroaryl ring (having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur), and a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring that is optionally bridged bicyclic or spirocyclic (having 1- 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) wherein the cyclic group is optionally substituted with one or more instances of R9; wherein the compound is not Compound X, wherein Compound X is defined herein.

[0009] Overexpression of CDK2 is associated with abnormal regulation of the cell-cycle. The cyclin E / CDK2 complex plays an important role in regulation of the G1 / S transition, histone biosynthesis and centrosome duplication. Progressive phosphorylation of retinoblastoma (Rb) by cyclin D / Cdk4 / 6 and cyclin E / Cdk2 releases the G1 transcription factor, E2F, and promotes S- phase entry. Activation of cyclin A / CDK2 during early S-phase promotes phosphorylation of endogenous substrates that permit DNA replication and inactivation of E2F, for S-phase completion. (Asghar et al., Nat. Rev. Drug. Discov.2015; 14(2): 130-146).

[0010] Cyclin E, the regulatory cyclin for CDK2, is frequently overexpressed in cancer. Cyclin E amplification or overexpression has long been associated with poor outcomes in breast cancer. (Keyomarsi et al., Cyclin E and survival in patients with breast cancer. N Engl J Med. (2002) 347:1566-75). Cyclin E2 (CCNE2) overexpression is associated with endocrine resistance in breast cancer cells and CDK2 inhibition has been reported to restore sensitivity to tamoxifen orCDK4 inhibitors in tamoxifen-resistant and CCNE2 overexpressing cells. (Caldon et al., Mol. Cancer Ther. (2012) 11:1488-99; Herrera-Abreu et al., Cancer Res. (2016) 76: 2301-2313). Cyclin E amplification also reportedly contributes to trastuzumab resistance in HER2+ breast cancer. (Scaltriti et al., Proc Natl Acad Sci. (2011) 108: 3761-6). Cyclin E overexpression has also been reported to play a role in basal-like and triple negative breast cancer (TNBC), as well as inflammatory breast cancer. (Elsawaf & Sinn, Breast Care (2011) 6:273-278; Alexander et al., Oncotarget (2017) 8: 14897-14911).

[0011] Amplification or overexpression of cyclin E1 (CCNE1) is also associated with poor outcomes in ovarian, gastric, endometrial and other cancers. (Nakayama et al., Gene amplification CCNE1 is related to poor survival and potential therapeutic target in ovarian cancer, Cancer (2010) 116: 2621-34; Etemadmoghadam et al., Clin Cancer Res (2013) 19: 5960-71; Au-Yeung et al., Clin. Cancer Res. (2017) 23:1862-1874; Ayhan et al., Modern Pathology (2017) 30: 297-303; Ooi et al., Hum Pathol. (2017) 61: 58-67; Noske et al., Oncotarget (2017) 8: 14794-14805).

[0012] There remains a need in the art for CDK inhibitors, especially selective CDK2 inhibitors, which may be useful for the treatment of cancer or other proliferative diseases or conditions. In particular, CDK2 inhibitors may be useful in treating CCNE1 or CCNE2 amplified tumors. 2. Compounds and Definitions:

[0013] Compounds of this present disclosure include those described generally herein, and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 101stEd. Additionally, general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 2005, and “March’s Advanced Organic Chemistry: Reactions Mechanisms and Structure”, 8thEd., Ed.: Smith, M.B., John Wiley & Sons, New York: 2019, the entire contents of which are hereby incorporated by reference.

[0014] The term “aliphatic” or “aliphatic group”, as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units ofunsaturation, but which is not aromatic (also referred to herein as “carbocycle,” “cycloaliphatic” or “cycloalkyl”), that has a single point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1 to 6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1 to 5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1 to 4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1 to 3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1 to 2 aliphatic carbon atoms. In some embodiments, “cycloaliphatic” (or “carbocycle” or “cycloalkyl”) refers to a monocyclic C3-C6hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

[0015] As used herein, the term “bicyclic ring” or “bicyclic ring system” refers to any bicyclic ring system, i.e. carbocyclic or heterocyclic, saturated or having one or more units of unsaturation, having one or more atoms in common between the two rings of the ring system. Thus, the term includes any permissible ring fusion, such as ortho-fused or spirocyclic. As used herein, the term “heterobicyclic” is a subset of “bicyclic” that requires that one or more heteroatoms are present in one or both rings of the bicycle. Such heteroatoms may be present at ring junctions and are optionally substituted, and may be selected from nitrogen (including N-oxides), oxygen, sulfur (including oxidized forms such as sulfones and sulfonates), phosphorus (including oxidized forms such as phosphonates and phosphates), boron, etc. In some embodiments, a bicyclic group has 7- 12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. As used herein, the term “bridged bicyclic” refers to any bicyclic ring system, i.e. carbocyclic or heterocyclic, saturated or partially unsaturated, having at least one bridge. “Bicyclic” may refer to a “bridged bicyclic” or “spirocyclic” ring. As used herein, “bridged bicyclic” rings are to be understood to be a subset of, and falling within the scope of, “bicyclic ring”. As defined by IUPAC, a “bridge” is an unbranched chain of atoms or an atom or a valence bond connecting two bridgeheads, where a “bridgehead” is any skeletal atom of the ring system which is bonded to three or more skeletal atoms (excluding hydrogen). In some embodiments, a bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Such bridged bicyclic groups are well known in the art and include those groups set forth belowwhere each group is attached to the rest of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise specified, a bridged bicyclic group is optionally substituted with one or more substituents as set forth for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted. Exemplary bicyclic rings include:

[0016] Exemplary bridged bicyclics, contemplated as falling under the scope of a “bicycle” or “bicyclic ring” include:

[0017] The term “Compound X” refers to 6-(1-benzyl-1H-pyrazole-4-carbonyl)-N-(3- (benzyloxy)-1-(methylamino)-1-oxobutan-2-yl)-2-(2,2-dimethylcyclopropane-1-carbonyl)-2,6- diazaspiro[3.4]octane-8-carboxamide. Compound X may also be depicted as.

[0018] The term “lower alkyl” refers to a C1-4straight or branched alkyl group. Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0019] The term “lower haloalkyl” refers to a C1-4straight or branched alkyl group that is substituted with one or more halogen atoms.

[0020] The term “heteroatom” means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen; or an oxygen, sulfur, nitrogen, phosphorus, or silicon atom in a heterocyclic ring.

[0021] The term “unsaturated,” as used herein, means that a moiety has one or more units of unsaturation.

[0022] As used herein, the term “bivalent C1-8(or C1-6) saturated or unsaturated, straight or branched, hydrocarbon chain,” refers to bivalent alkylene, alkenylene, and alkynylene chains that are straight or branched as defined herein.

[0023] The term “alkylene” refers to a bivalent alkyl group. An “alkylene chain” is a polymethylene group, i.e., –(CH2)n–, wherein n is a positive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.

[0024] The term “alkenylene” refers to a bivalent alkenyl group. A substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.

[0025] The term “halogen” means F, Cl, Br, or I.

[0026] The term “aryl” used alone or as part of a larger moiety as in “aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to monocyclic or bicyclic ring systems having a total of 4 to 14 ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains three to seven ring members. The term “aryl” may be used interchangeably with the term “aryl ring”. In certain embodiments of the present disclosure, “aryl” refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents. Also included within the scope of the term “aryl,” as it is used herein, is a group in which an aromatic ring is fused to one or more non–aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like.

[0027] The terms “heteroaryl” and “heteroar–,” used alone or as part of a larger moiety, e.g., “heteroaralkyl,” or “heteroaralkoxy,” refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 π electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms. The term “heteroatom” in the context of “heteroaryl” particularly includes, but is not limited to, nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen. Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. The terms “heteroaryl” and “heteroar–”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring. Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H–quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3–b]–1,4–oxazin–3(4H)–one. A heteroaryl group may be monocyclic or bicyclic. A heteroaryl ring may include one or more oxo (=O) or thioxo (=S) substituent. The term “heteroaryl” may be used interchangeably with the terms “heteroaryl ring,” “heteroaryl group,” or “heteroaromatic,” any of which terms include rings that are optionally substituted. The term “heteroaralkyl” refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted.

[0028] As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclic radical,” and “heterocyclic ring” are used interchangeably and refer to a stable 5– to 7–membered monocyclic or 7 to 10–membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably 1 to 4, heteroatoms, as defined above. When used in reference to a ring atom of a heterocycle, the term “nitrogen” includes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring (having 0 to 3 heteroatoms selected from oxygen, sulfur and nitrogen.

[0029] A heterocyclic ring can be attached to a provided compound at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The terms “heterocycle,” “heterocyclyl,” “heterocyclyl ring,” “heterocyclic group,” “heterocyclic moiety,” and “heterocyclic radical,” are used interchangeably herein, and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3H–indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl. A heterocyclyl group may be monocyclic or bicyclic, bridged bicyclic, or spirocyclic. A heterocyclic ring may include one or more oxo (=O) or thioxo (=S) substituent. The term “heterocyclylalkyl” refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.

[0030] As used herein, the term “partially unsaturated” refers to a ring moiety that includes at least one double or triple bond. The term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as herein defined.

[0031] As described herein, compounds of the present disclosure may contain “substituted” moieties. In general, the term “substituted” means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at one or more substitutable position of the group, and when more than one position in any given structure is substituted with more than onesubstituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by the present disclosure are preferably those that result in the formation of stable or chemically feasible compounds. The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0032] Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group are independently halogen; –(CH2)0–6R°; –(CH2)0–6OR°; –O(CH2)0–6R°, –O– (CH2)0–6C(O)OR°; –(CH2)0–6CH(OR°)2; –(CH2)0–6SR°; –(CH2)0–6Ph, which Ph may be substituted with R°; –(CH2)0–46O(CH2)0–1Ph which Ph may be substituted with R°; –CH=CHPh, which Ph may be substituted with R°; –(CH2)0–6O(CH2)0–1-pyridyl which pyridyl may be substituted with R°; –NO2; –CN; –N3; –(CH2)0–6N(R°)2; –(CH2)0–6N(R°)C(O)R°; –N(R°)C(S)R°; –(CH2)0–6N(R°)C(O)NR°2; –N(R°)C(S)NR°2; –(CH2)0–6N(R°)C(O)OR°; –N(R°)N(R°)C(O)R°; – N(R°)N(R°)C(O)NR°2; –N(R°)N(R°)C(O)OR°; –(CH2)0–6C(O)R°; –C(S)R°; –(CH2)0–6C(O)OR°; –(CH2)0–6C(O)SR°; –(CH2)0–6C(O)OSiR°3; –(CH2)0–6OC(O)R°; –OC(O)(CH2)0–6SR°,–(CH2)0–6SC(O)R°; –(CH2)0–6C(O)NR°2; –C(S)NR°2; –C(S)SR°; –SC(S)SR°, –(CH2)0–6OC(O)NR°2; -C(O)N(OR°)R°; –C(O)C(O)R°; –C(O)CH2C(O)R°; –C(NOR°)R°; –(CH2)0–6SSR°; –(CH2)0–6S(O)2R°; –(CH2)0–6S(O)2OR°; –(CH2)0–6OS(O)2R°; –S(O)2NR°2; –(CH2)0–6S(O)R°; –N(R°)S(O)2NR°2; –N(R°)S(O)2R°; –N(OR°)R°; –C(NH)NR°2; –P(O)2R°; –P(O)R°2; – P(O)(OR°)2; –OP(O)(R°)OR°; –OP(O)R°2; –OP(O)(OR°)2; SiR°3; –(C1–4straight or branched alkylene)O–N(R°)2; or –(C1–4straight or branched alkylene)C(O)O–N(R°)2, wherein each R° may be substituted as defined below and is independently hydrogen, C1–6aliphatic, –CH2Ph, –O(CH2)0–1Ph, –CH2–(5- to 6-membered heteroaryl ring), –CH2–(5- to 6-membered saturated or partially unsaturated monocyclic heterocyclic ring [having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur]), or a 3- to 6-membered saturated, partially unsaturated, or aryl ring (having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), or, notwithstanding the definition above, two independent occurrences of R°, taken together with their intervening atom(s), form a 3- to 12-membered saturated, partially unsaturated, or aryl mono– or bicyclic ring (having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), which may be substituted as defined below. An “optionally substituted” group may be substitutedwith one or more (i.e., from 1 to 6) substituents selected from the aforementioned monovalent substituents and one or more (i.e., from 1 to 6) suitable divalent substituents of =O, =S, =NNR°2, =NNHC(O)R°, =NNHC(O)OR°, =NNHS(O)2R°, =NR°, =NOR°, –O(C(R°2))2–3O–, –(C(R°)2)2–6– , and –S(C(R°2))2–3S–, wherein each of the one or more substituents is independently selected from said monovalent substituents and divalent substituents, and wherein said divalent substituents may be on a saturated carbon of an “optionally substituted” group.

[0033] Suitable monovalent substituents on R° (or the ring formed by taking two independent occurrences of R° together with their intervening atoms), wherein R° may be substituted with one or more instances of said monovalent substituents (i.e., from 1 to 6) and suitable divalent substituents described at the end of this paragraph, and said monovalent substituents are each independently halogen, –(CH2)0–2R●, –(haloR●), –(CH2)0–2OH, –(CH2)0–2OR●, –(CH2)0–2CH(OR●)2; -O(haloR●), –CN, –N3, –(CH2)0–2C(O)R●, –(CH2)0–2C(O)OH, –(CH2)0–2C(O)OR●, – (CH2)0–2SR●, –(CH2)0–2SH, –(CH2)0–2NH2, –(CH2)0–2NHR●, –(CH2)0–2NR●2, –NO2, –SiR●3, – OSiR●3, -C(O)SR●, –(C1–4straight or branched alkylene)C(O)OR●, or –SSR●wherein each R●is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from C1–4aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5 to 6–membered saturated, partially unsaturated, or aryl ring (having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). Suitable divalent substituents on a saturated carbon atom of R° include =O and =S.

[0034] Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group include the following: =O, =S, =NNR*2, =NNHC(O)R*, =NNHC(O)OR*, =NNHS(O)2R*, =NR*, =NOR*, –O(C(R*2))2–3O–, or –S(C(R*2))2–3S–, wherein each independent occurrence of R*is selected from hydrogen, C1–6aliphatic which may be substituted as defined below, and an unsubstituted 5 to 6–membered saturated, partially unsaturated, or aryl ring (having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: –O(CR*2)2–3O–, wherein each independent occurrence of R*is selected from hydrogen, C1–6aliphatic which may be substituted as defined below, and an unsubstituted 5 to 6–membered saturated, partially unsaturated, or aryl ring (having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur).

[0035] Suitable substituents on the aliphatic group of R*include halogen, –R●, -(haloR●), -OH, – OR●, –O(haloR●), –CN, –C(O)OH, –C(O)OR●, –NH2, –NHR●, –NR●2, or –NO2, wherein each R●is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1–4aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5 to 6–membered saturated, partially unsaturated, or aryl ring (having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur).

[0036] Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include –R†, –NR†2, –C(O)R†, –C(O)OR†, –C(O)C(O)R†, – C(O)CH2C(O)R†, -S(O)2R†, -S(O)2NR†2, –C(S)NR†2, –C(NH)NR†2, or –N(R†)S(O)2R†; wherein each R†is independently hydrogen, C1–6aliphatic which may be substituted as defined below, unsubstituted –OPh, or an unsubstituted 5 to 6–membered saturated, partially unsaturated, or aryl ring (having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), or, notwithstanding the definition above, two independent occurrences of R†, taken together with their intervening atom(s) form an unsubstituted 3 to 12–membered saturated, partially unsaturated, or aryl mono– or bicyclic ring (having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur).

[0037] Suitable substituents on the aliphatic group of R†are independently halogen, – R●, -(haloR●), –OH, –OR●, –O(haloR●), –CN, –C(O)OH, –C(O)OR●, –NH2, –NHR●, –NR●2, or -NO2, wherein each R●is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1–4aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5 to 6– membered saturated, partially unsaturated, or aryl ring (having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur).

[0038] As used herein, the term “provided compound” or “compound of the present disclosure” refers to any genus, subgenus, and / or species set forth herein.

[0039] “One or more instances” or “one or more” as referencing substitutions, as used herein, refers to, for example, 1, 2, 3, 4, 5, 6, 7, etc. instances of substitution of functional groups, which may each be independently selected, on a chemical moiety to which “one or more” instances of substitution refers. It is to be understood that any “optionally substituted” moiety, may be substituted with “one or more” optional substituents each independently selected from those optional substituents as described herein.

[0040] As used herein, the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1–19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this disclosure include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2– hydroxy–ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2–naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3–phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p–toluenesulfonate, undecanoate, valerate salts, and the like.

[0041] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C1–4alkyl)4salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[0042] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the presentcompounds are within the scope of the disclosure. Unless otherwise stated, all tautomeric forms of the compounds of the disclosure are within the scope of the disclosure. Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a13C- or14C-enriched carbon are within the scope of this disclosure. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present disclosure.

[0043] As used herein, the term “inhibitor” is defined as a compound that binds to and / or inhibits CDK2 with measurable affinity. In certain embodiments, an inhibitor has an IC50and / or binding constant of less than about 50 μM, less than about 1 μM, less than about 500 nM, less than about 100 nM, less than about 10 nM, or less than about 1 nM, when measured in an appropriate assay.

[0044] The term “patient,” as used herein, means an animal, preferably a mammal, and most preferably a human.

[0045] The term “pharmaceutically acceptable carrier, adjuvant, or vehicle” refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of this disclosure include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

[0046] A “pharmaceutically acceptable derivative” means any non-toxic salt, ester, salt of an ester or other derivative of a compound of this disclosure that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this disclosure or an inhibitorily or degratorily active metabolite or residue thereof.

[0047] As used herein, the term "inhibitorily active metabolite or residue thereof" means that a metabolite or residue thereof is also an inhibitor of a CDK2 protein, or a mutant thereof. 3. Description of Exemplary Embodiments:

[0048] In certain embodiments, the present disclosure provides inhibitors of CDK2 activity.

[0049] In some embodiments, the inhibitors of CDK2 include compounds of Formula IA:or a pharmaceutically acceptable salt thereof, wherein: RAisRBis hydrogen, an optionally substituted C1-6aliphatic group, -OR, -NR2or a halogen; L1is a covalent bond or a saturated or unsaturated, straight or branched, optionally substituted bivalent C1-6hydrocarbon chain, wherein 0-2 methylene units of L1are independently replaced by -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -C(S)-, -NRS(O)2-, - S(O)2NR-, -NRC(O)-, -C(O)NR-, -OC(O)NR-, -NRC(O)O-, or -NRC(O)NR-; R1is hydrogen, an optionally substituted C1-6aliphatic group, or an optionally substituted cyclic group selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring that is optionally bridged bicyclic or spirocyclic (having 1-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur), a 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and an 8-10 membered bicyclic heteroaromatic ring (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur); R2is hydrogen, an optionally substituted C1-6aliphatic group, –C1-6alkylene-OR,–C1-3alkylene-O-C1-3alkylene-R,–C(O)OR, –C(O)NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -P(O)R2, – C(O)NRS(O)2R, or an optionally substituted cyclic group selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and an 8-10 membered bicyclic heteroaromatic ring (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur); and R3is hydrogen; or R2and R3together with the intervening carbon atom form an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring, or an optionally substituted 3-7 membered saturated or partially unsaturated heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur); R4is an optionally substituted cyclic group selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and an 8-10 membered bicyclic heteroaromatic ring (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur); and R5is hydrogen; orR4and R5together with the intervening nitrogen atom form an optionally substituted 4-7 membered saturated, or partially unsaturated heterocyclic ring (having 0-2 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur), or an optionally substituted heteroaryl ring (having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur); L2is a saturated or unsaturated, straight or branched, optionally substituted bivalent C1-4hydrocarbon chain, wherein 0-2 methylene units of L2are independently replaced by -O-, -NR-, - S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -C(S)-, -NRS(O)2-, -S(O)2NR-, -NRC(O)-, - C(O)NR-, -OC(O)NR-, -NRC(O)O-, or -NRC(O)NR-; R6is an optionally substituted C1-6aliphatic group, or a cyclic group selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and an 8-10 membered bicyclic heteroaromatic ring (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the cyclic group is optionally substituted with one or more instances of R7; each instance of R7is independently halogen, –CN, –NO2, –OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, –C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, –N(R)S(O)2R, an optionally substituted C1-6aliphatic group, an optionally substituted C1-6aliphatic-Cy group, or Cy; L3is a saturated or unsaturated, straight or branched, optionally substituted bivalent C1-4hydrocarbon chain, wherein 0-2 methylene units of L3are independently replaced by -O-, -NR-, - S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -C(S)-, -NRS(O)2-, -S(O)2NR-, -NRC(O)-, - C(O)NR-, -OC(O)NR-, -NRC(O)O-, or -NRC(O)NR-; R8is a cyclic group selected from a 3-8 membered saturated or partially unsaturatedmonocyclic carbocyclic ring, a 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and an 8-10 membered bicyclic heteroaromatic ring (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the cyclic group is optionally substituted with one or more instances of R9; each instance of R9is independently halogen, –CN, –NO2, –OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, –C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, –N(R)S(O)2R, an optionally substituted C1-6aliphatic group, an optionally substituted C1-6aliphatic-Cy group, or Cy; each Cy is independently an optionally substituted cyclic group selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and a 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); and each R is independently hydrogen, or an optionally substituted C1-6aliphatic group, an optionally substituted phenyl, an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring, an optionally substituted 3-7 membered saturated or partially unsaturated heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), or an optionally substituted 5-6 membered heteroaryl ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); or when there are two R groups on the same nitrogen they are taken together with their intervening atoms to form a cyclic group selected from a 4-7 membered saturated, partiallyunsaturated, or heteroaryl ring (having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur), and a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring that is optionally bridged bicyclic or spirocyclic (having 1- 4 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur) wherein the cyclic group is optionally substituted with one or more instances of R9; and wherein the compound is not Compound X, wherein Compound X is defined herein.

[0050] In some embodiments, the inhibitors of CDK2 include compounds of Formula I:or a pharmaceutically acceptable salt thereof, wherein: RAisL1is a covalent bond or a saturated or unsaturated, straight or branched, optionally substituted bivalent C1-6hydrocarbon chain, wherein 0-2 methylene units of L1are independently replaced by -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -C(S)-, -NRS(O)2-, - S(O)2NR-, -NRC(O)-, -C(O)NR-, -OC(O)NR-, -NRC(O)O-, or -NRC(O)NR-; R1is hydrogen, an optionally substituted C1-6aliphatic group, or an optionally substituted cyclic group selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring that is optionally bridged bicyclic or spirocyclic (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 5-6 membered monocyclicheteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and an 8-10 membered bicyclic heteroaromatic ring (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur); R2is an optionally substituted C1-6aliphatic group, –C1-6alkylene-OR,–C(O)OR, – C(O)NR2, –C(O)NRS(O)2R, or an optionally substituted cyclic group selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and a 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); and R3is hydrogen; R4and R5together with the intervening nitrogen atom form an optionally substituted 4-7 membered saturated, or partially unsaturated heterocyclic ring (having 0-2 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur), or an optionally substituted heteroaryl ring (having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur); L2is a saturated or unsaturated, straight or branched, optionally substituted bivalent C1-4hydrocarbon chain, wherein 0-2 methylene units of L2are independently replaced by -O-, -NR-, - S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -C(S)-, -NRS(O)2-, -S(O)2NR-, -NRC(O)-, - C(O)NR-, -OC(O)NR-, -NRC(O)O-, or -NRC(O)NR-; R6is an optionally substituted C1-6aliphatic group, or a cyclic group selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and an 8-10 membered bicyclic heteroaromatic ring (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the cyclic group is optionally substituted with one or more instances of R7;each instance of R7is independently halogen, –CN, –NO2, –OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, –C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, –N(R)S(O)2R, an optionally substituted C1-6aliphatic group, an optionally substituted C1-6aliphatic-Cy group, or Cy; L3is a saturated or unsaturated, straight or branched, optionally substituted bivalent C1-4hydrocarbon chain, wherein 0-2 methylene units of L3are independently replaced by -O-, -NR-, - S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -C(S)-, -NRS(O)2-, -S(O)2NR-, -NRC(O)-, - C(O)NR-, -OC(O)NR-, -NRC(O)O-, or -NRC(O)NR-; R8is a cyclic group selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and an 8-10 membered bicyclic heteroaromatic ring (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the cyclic group is optionally substituted with one or more instances of R9; each instance of R9is independently halogen, –CN, –NO2, –OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, –C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, –N(R)S(O)2R, an optionally substituted C1-6aliphatic group, an optionally substituted C1-6aliphatic-Cy group, or Cy; each Cy is independently an optionally substituted cyclic group selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring (having 1-4 heteroatoms independently selected fromnitrogen, oxygen, and sulfur), and a 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); and each R is independently hydrogen, or an optionally substituted C1-6aliphatic group, an optionally substituted phenyl, an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring, an optionally substituted 3-7 membered saturated or partially unsaturated heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), or an optionally substituted 5-6 membered heteroaryl ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); or when there are two R groups on the same nitrogen they are taken together with their intervening atoms to form a cyclic group selected from a 4-7 membered saturated, partially unsaturated, or heteroaryl ring (having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur), and a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring that is optionally bridged bicyclic or spirocyclic (having 1- 4 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur) wherein the cyclic group is optionally substituted with one or more instances of R9; and wherein the compound is not Compound X, wherein Compound X is defined herein.

[0051] As defined generally above, RAis. In some embodiments, RAis In some embodiments,A AR isIn some embodiments, R iswherein the R group shown is an optionally substituted C1-6aliphatic group. In some embodiments, RAiswherein the R group shown is an optionally substitutedmethyl group. In some embodiments, RAisAIn some embodiments, R iswherein R4and R5together with the intervening nitrogen atom form an optionally substituted 4-7 membered saturated, or partially unsaturated heterocyclic ring (having 0-2 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur). In some embodiments, RAis selected from those depicted in the compounds of Table 1, below.

[0052] As defined generally above, RBis hydrogen, an optionally substituted C1-6aliphatic group, -OR, -NR2or a halogen. In some embodiments, RBis hydrogen. In some embodiments, RBis an optionally substituted C1-6aliphatic group. In some embodiments, RBis -OR. In some embodiments, RBis -NR2. In some embodiments, RBis a halogen. In some embodiments, RBis a methyl group. In some embodiments, RBis a fluoro group. In some embodiments, RBis selected from those depicted in the compounds of Table 1, below.

[0053] As defined generally above, L1is a covalent bond or a saturated or unsaturated, straight or branched, optionally substituted bivalent C1-6hydrocarbon chain, wherein 0-2 methylene units of L1are independently replaced by -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, - C(S)-, -NRS(O)2-, -S(O)2NR-, -NRC(O)-, -C(O)NR-, -OC(O)NR-, -NRC(O)O-, or -NRC(O)NR- .

[0054] In some embodiments, L1is a covalent bond. In some embodiments, L1is a saturated or unsaturated, straight or branched, optionally substituted bivalent C1-6hydrocarbon chain, wherein 0-2 methylene units of L1are independently replaced by -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)- , -S(O)-, -S(O)2-, -C(S)-, -NRS(O)2-, -S(O)2NR-, -NRC(O)-, -C(O)NR-, -OC(O)NR-, -NRC(O)O- , or -NRC(O)NR-. In some embodiments, L1is a saturated or unsaturated, straight or branched, optionally substituted bivalent C1-4hydrocarbon chain, wherein 0-2 methylene units of L are independently replaced by -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -C(S)-, - NRS(O)2-, -S(O)2NR-, -NRC(O)-, -C(O)NR-, -OC(O)NR-, -NRC(O)O-, or -NRC(O)NR-. In some embodiments, L1is a saturated or unsaturated, straight or branched, optionally substituted bivalent C1-4hydrocarbon chain. In some embodiments, L1is a saturated or unsaturated, straight or branched, optionally substituted bivalent C1-4hydrocarbon chain, wherein 1 or 2 methylene units of L1are replaced by -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -C(S)-, -NRS(O)2-, -S(O)2NR-, -NRC(O)-, -C(O)NR-, -OC(O)NR-, -NRC(O)O-, or -NRC(O)NR-. In some embodiments, L1is a saturated, straight or branched, optionally substituted bivalent C1-4hydrocarbon chain. In some embodiments, L1is a partially unsaturated, straight or branched, optionally substituted bivalent C1-4hydrocarbon chain. In some embodiments, L1is a saturated, straight, optionally substituted bivalent C1-4hydrocarbon chain, wherein 1-2 methylene units of L1are independently replaced by -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -C(S)-, -NRS(O)2-, -S(O)2NR-, -NRC(O)-, -C(O)NR-, -OC(O)NR-, -NRC(O)O-, or -NRC(O)NR-. In some embodiments, L1is an optionally substituted straight or branched C1-4alkylene chain, wherein 1-2 methylene units of L1are independently replaced by -O-, -NR-, -S-, -C(O)O-, -C(O)- , -S(O)2-, or -NRC(O)-. In some embodiments, L1is an optionally substituted straight or branched C1-4alkylene chain, wherein 1-2 methylene units of L1are independently replaced by -O-, -NR-, - C(O)O-, -C(O)-, or -NRC(O)-. In some embodiments, L1is an optionally substituted straight or branched C1-4alkylene chain, wherein 1-2 methylene units of L1are independently replaced by - O-, -NR-, -C(O)O-, or -NRC(O)-. In some embodiments, L1is an optionally substituted straight or branched C1-4alkylene chain, wherein 1-2 methylene units of L1are independently replaced by -O-. In some embodiments, L1is an optionally substituted straight or branched C1-4alkylene chain, wherein 1-2 methylene units of L1are independently replaced by -S-. In some embodiments, L1is an optionally substituted straight or branched C1-4alkylene chain, wherein 1-2 methylene units of L1are independently replaced by –S(O)2-. In some embodiments, L1is an optionally substituted straight or branched C1-4alkylene chain, wherein 1-2 methylene units of L1are independently replaced by -NR-. In some embodiments, L1is an optionally substituted straight or branched C1-4alkylene chain, wherein 1-2 methylene units of L1are independently replaced by –C(O)O-. In some embodiments, L1is an optionally substituted straight or branched C1-4alkylene chain, wherein 1-2 methylene units of L1are independently replaced by –NRC(O)-. In some embodiments, L1is an unsubstituted straight chain C1-4alkynylene.

[0055] In some embodiments, L1is a covalent bond,In some embodim1ents, L isor

[0056] In some embodiments, L1is

[0057] In some embodiments, L1is selected from those depicted in the compounds of Table 1, below.

[0058] As defined generally above, R1is hydrogen, an optionally substituted C1-6aliphatic group, or an optionally substituted cyclic group selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring that is optionally bridged bicyclic or spirocyclic (having 1- 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and an 8-10 membered bicyclic heteroaromatic ring (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur).

[0059] In some embodiments, R1is hydrogen. In some embodiments, R1is an optionally substituted C1-6aliphatic group. In some embodiments, R1is methyl. In some embodiments, R1is ethyl. In some embodiments, R1is isopropyl.

[0060] In some embodiments, R1is an optionally substituted cyclic group selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring that is optionally bridged bicyclic or spirocyclic (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and an 8-10 membered bicyclic heteroaromatic ring (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R1is an optionally substituted cyclic group selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and an 8-10 membered bicyclic heteroaromatic ring (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R1is an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R1is an optionally substituted phenyl. In some embodiments, R1is an optionally substituted 8-10 membered bicyclic aromatic carbocyclic ring. In some embodiments, R1is an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R1is an optionally substituted 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R1is an optionally substituted 8-10 membered bicyclic heteroaromatic ring (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R1is an optionally substituted cyclic group selected from phenyl, cyclohexyl, cyclopentyl, cyclobutyl,cyclopropyl, cycloheptyl, oxazolyl, pyridinyl, pyridazinyl, 1,3,4-oxadiazolyl, 1,2,3-triazolyl, pyrazolyl, and tetrahydropyranyl. In some embodiments, R1is optionally substituted phenyl. In some embodiments, R1is optionally substituted cyclohexyl.

[0061] In some embodiments, R1is an optionally substituted 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring that is optionally bridged bicyclic or spirocyclic (having 1- 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R1is an optionally substituted a 7-12 membered saturated or partially unsaturated bridged bicyclic carbocyclic ring. In some embodiments, R1is an optionally substituted 7-12 membered bridge bicyclic carbocyclic ring or an optionally substituted 7-12 membered bridged bicyclic heterocyclic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R1is optionally substituted oxabicyclo[2.2.2]octanyl. In some embodiments, R1is optionally substituted bicyclo[2.2.2]octanyl.

[0062] In some embodiments, R1isIn some embodiments, R1is

[0063] In some embodiments, R1is selected from those depicted in the compounds of Table 1, below.

[0064] As defined generally above, R2is hydrogen, an optionally substituted C1-6aliphatic group, –C1-6alkylene-OR,–C1-3alkylene-O-C1-3alkylene-R,–C(O)OR, – C(O)NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -P(O)R2, –C(O)NRS(O)2R, or an optionally substituted cyclic group selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur), and an 8-10 membered bicyclic heteroaromatic ring (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur); and R3is hydrogen; or R2and R3together with the intervening carbon atom form an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring, or an optionally substituted 3-7 membered saturated or partially unsaturated heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur).

[0065] In some embodiments, R2is hydrogen, an optionally substituted C1-6aliphatic group, –C1-6alkylene-OR,–C1-3alkylene-O-C1-3alkylene-R,–C(O)OR, or –C(O)NR2; and R3is hydrogen; or R2and R3together with the intervening carbon atom form an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring, or an optionally substituted 3-7 membered saturated or partially unsaturated heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur).

[0066] Alternatively, R2is hydrogen, an optionally substituted C1-6aliphatic group, –C1-6alkylene- OR,–C1-3alkylene-O-C1-3alkylene-R,–C(O)OR, –C(O)NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -P(O)R2, –C(O)NRS(O)2R, or an optionally substituted cyclic group selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and an 8-10 membered bicyclic heteroaromatic ring (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur); and R3is hydrogen; or R2and R3together with the intervening carbon atom form an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring, or an optionally substituted 3-7 membered saturated or partially unsaturated heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur).

[0067] In some embodiments, R2is hydrogen, an optionally substituted C1-6aliphatic group, –C1-6alkylene-OR,–C1-3alkylene-O-C1-3alkylene-R, –C(O)OR, –C(O)NR2, -S(O)2R,-S(O)2NR2, -S(O)R, -P(O)R2, –C(O)NRS(O)2R, or an optionally substituted cyclic group selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and an 8-10 membered bicyclic heteroaromatic ring (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur); and R3is hydrogen.

[0068] In some embodiments, R2is an optionally substituted C1-6aliphatic group, –C1-6alkylene- OR,–C(O)OR, –C(O)NR2, –C(O)NRS(O)2R, or an optionally substituted cyclic group selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, a 3- 8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and a 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); and R3is hydrogen.

[0069] In some embodiments, R2is an optionally substituted C1-6aliphatic group, –C1-6alkylene- OR, –C(O)OR, –C(O)NR2, –C(O)NRS(O)2R, or an optionally substituted phenyl; and R3is hydrogen.

[0070] In some embodiments, R2is hydrogen, an optionally substituted C1-6aliphatic group, -C1-6alkylene-OR, –C1-3alkylene-O-C1-3alkylene-R, –C(O)OR, or –C(O)NR2; and R3is hydrogen. In some embodiments, R2is hydrogen, methyl, –CH2OR,–CH2OCH2R,–C(O)OR, or –C(O)NR2; and R3is hydrogen. In some embodiments, R2is hydrogen. In some embodiments, R2is an optionally substituted C1-6aliphatic group. In some embodiments, R2is methyl. In some embodiments, R2is -C1-6alkylene-OR. In some embodiments, R2is –CH2OR. In some embodiments, R2is –CH2OCH2R. In some embodiments, R2is –C(O)OR. In some embodiments, R2is –C(O)NR2. In some embodiments, R2is –C(O)NR2, wherein the two R groups, taken together with the intervening nitrogen atom, form an optionally substituted 4-7 membered saturated, partially unsaturated, or heteroaryl ring (having 0-3 heteroatoms, in addition to the nitrogen,independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R2is – C(O)NR2, wherein the two R groups, taken together with the intervening nitrogen atom, form an optionally substituted 4-7 membered saturated ring (having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R2is –C(O)NR2, wherein the two R groups, taken together with the intervening nitrogen atom, form an optionally substituted 4-7 membered saturated ring, selected from a piperidinyl, morpholinyl, piperazinyl, azetindinyl, pyrrolidinyl, azaspiro[3.3]heptanyl, and diazaspiro[3.3]heptanyl.

[0071] In some embodiments, R2is -S(O)2R, -S(O)2NR2, -S(O)R, or -P(O)R2. In some embodiments, R2is -S(O)2R. In some embodiments, R2is -S(O)2NR2. In some embodiments, R2is -S(O)R. In some embodiments, R2is -P(O)R2. In some embodiments, R2is -S(O2)CH3. In some embodiments, R2is -P(O)(CH3)2.

[0072] In some embodiments, R2is an optionally substituted cyclic group selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and an 8-10 membered bicyclic heteroaromatic ring (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R2is an optionally substituted cyclic group selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and an 8-10 membered bicyclic heteroaromatic ring (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R2is an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R2is an optionally substituted phenyl. In some embodiments, R2is an optionally substituted 8-10 membered bicyclic aromatic carbocyclic ring. In someembodiments, R2is an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R2is an optionally substituted 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R2is an optionally substituted 8-10 membered bicyclic heteroaromatic ring (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R2is a tetrahydrofuranyl. In some embodiments, R2is a dioxanyl. In some embodiments, R2is a furanyl. In some embodiments, R2is an oxadiazolyl. In some embodiments, R2is an oxazolyl.

[0073] In some embodiments, R2is selected from those depicted in the compounds of Table 1, below.

[0074] In some embodiments, R3is hydrogen and R2is a substituent in Table A: Table A. Exemplary R2substituents

[0075] In some embodiments, R2and R3together with the intervening carbon atom form an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring, or anoptionally substituted 3-7 membered saturated or partially unsaturated heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R2and R3together with the intervening carbon atom form an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring. In some embodiments, R2and R3together with the intervening carbon atom form an optionally substituted 3-7 membered saturated carbocyclic ring. In some embodiments, R2and R3together with the intervening carbon atom form an optionally substituted 3-7 membered saturated or partially unsaturated heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R2and R3together with the intervening carbon atom form an optionally substituted 3-7 membered saturated heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R2and R3together with the intervening carbon atom form an optionally substituted oxetanyl, cyclopropyl, cyclobutyl, cyclopentyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, or 1,4-oxazepanyl. In some embodiments, R2and R3form a cyclic group selected from those depicted in the compounds of Table 1, below.

[0076] As defined generally above, R4is an optionally substituted cyclic group selected from a 3- 8 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and an 8-10 membered bicyclic heteroaromatic ring (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and R5is hydrogen; or R4and R5together with the intervening nitrogen atom form an optionally substituted 4-7 membered saturated, or partially unsaturated heterocyclic ring (having 0-2 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur), or an optionally substituted heteroaryl ring (having 0-3 heteroatoms, independently selected from nitrogen, oxygen, and sulfur).

[0077] In some embodiments, R4is an optionally substituted cyclic group selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and an 8-10 membered bicyclic heteroaromatic ring (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and R5is hydrogen. In some embodiments, R4is an optionally substituted cyclic group selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and a 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R4is an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R4is an optionally substituted 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring. In some embodiments, R4is an optionally substituted phenyl. In some embodiments, R4is an optionally substituted 8-10 membered bicyclic aromatic carbocyclic ring. In some embodiments, R4is an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R4is an optionally substituted 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R4is an optionally substituted cyclic group selected from phenyl, piperidinyl, tetrahydropyranyl, 1,4-oxazepanyl, oxazolyl, cyclobutyl, cyclopentyl, or pyrrolidinyl. In some embodiments, R4is selected from those depicted in the compounds of Table 1, below.

[0078] In some embodiments, R4and R5together with the intervening nitrogen atom form an optionally substituted 4-7 membered saturated, or partially unsaturated heterocyclic ring (having 0-2 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, andsulfur), or an optionally substituted heteroaryl ring (having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R4and R5together with the intervening nitrogen atom form an optionally substituted 4-7 membered saturated, or partially unsaturated heterocyclic ring (having 0-2 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R4and R5together with the intervening nitrogen atom form an optionally substituted heteroaryl ring (having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur).

[0079] In some embodiments, R4and R5together with the intervening nitrogen atom form an optionally substituted 6 membered saturated heterocyclic ring (having 0 or 1 additional nitrogen atoms, in addition to the intervening nitrogen). In some embodiments, R4and R5together with the intervening nitrogen atom form an optionally substituted 6 membered saturated heterocyclic ring. In some embodiments, R4and R5together with the intervening nitrogen atom form an optionally substituted 6 membered saturated heterocyclic ring (having 1 additional nitrogen atom, in addition to the intervening nitrogen).

[0080] In some embodiments, R4and R5together with the intervening nitrogen atom form an optionally substituted cyclic group selected from piperindinyl, piperazinyl, morpholinyl, and pyrrolidinyl. In some embodiments, R4and R5together with the intervening nitrogen atom form a substituted cyclic group, wherein the cyclic group is substituted with one or more groups selected from –C1-6alkylene-phenyl, –O-C1-6alkylene-phenyl, –C1-6alkylene-cyclohexyl, –O-C1-6alkylene- cyclohexyl, –C1-6alkylene-COOH, –C1-6alkylene-C(O)O-(C1-4alkyl), –C1-6alkylene- C(O)NHS(O)2-(C1-4alkyl). In some embodiments, R4and R5form a cyclic group selected from those depicted in the compounds of Table 1, below.

[0081] In some embodiments, RAis a substituent of Table B: Table B: Exemplary RAsubstituents

[0082] In some embodiments, RAisIn some embodiments, RAis

[0083] As defined generally above, L2is a saturated or unsaturated, straight or branched, optionally substituted bivalent C1-4hydrocarbon chain, wherein 0-2 methylene units of L2are independently replaced by -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -C(S)-, - NRS(O)2-, -S(O)2NR-, -NRC(O)-, -C(O)NR-, -OC(O)NR-, -NRC(O)O-, or -NRC(O)NR-.

[0084] In some embodiments, L2is a saturated or unsaturated, straight or branched, optionally substituted bivalent C1-4hydrocarbon chain, wherein 0-2 methylene units of L2are independently replaced by -C(O)O-, -C(O)-, or -C(O)NR-. In some embodiments, L2is a C1-4alkylene chain, wherein 1-2 methylene units of L2are independently replaced by -C(O)O-, -C(O)-, or -C(O)NR-. In some embodiments, L2is C1-4 alkylene chain, wherein 1 methylene unit of L2is replaced by - C(O)O-, -C(O)-, or -C(O)NR-. In some embodiments, L2is a saturated optionally substituted bivalent C1-4hydrocarbon chain. In some embodiments, L2is a saturated bivalent C1-4hydrocarbon chain, substituted on a single methylene unit by two substituents, which together with the intervening carbon atom form a 3-7 membered carbocyclic ring or heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, L2is, or In some embodi2ments, L isIn some embodim2ents, L isor In some embodiments, L2is In some embodiment2s, L is selected from thosedepicted in the compounds of Table 1, below.

[0085] In some embodiments, L2is a saturated, straight or branched, optionally substituted bivalent C1-4hydrocarbon chain. In some embodiments, L2is methylene.

[0086] In some embodiments, L2is -S(O)2-.

[0087] As defined generally above, R6is an optionally substituted C1-6aliphatic group, or a cyclic group selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclicring, a 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring, phenyl, an 8- 10 membered bicyclic aromatic carbocyclic ring, a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and an 8-10 membered bicyclic heteroaromatic ring (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the cyclic group is optionally substituted with one or more instances of R7.

[0088] In some embodiments, R6is an optionally substituted C1-6aliphatic group. In some embodiments, R6is an optionally substituted methyl, ethyl, isopropyl, or tert-butyl group.

[0089] In some embodiments, R6is a cyclic group selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and an 8-10 membered bicyclic heteroaromatic ring (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the cyclic group is optionally substituted with one or more instances of R7. In some embodiments, R6is a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, optionally substituted with one or more instances of R7. In some embodiments, R6is a phenyl group, optionally substituted with one or more instances of R7. In some embodiments, R6is a cyclic group selected from cyclopropyl, cyclobutyl, cyclohexyl and phenyl, wherein the cyclic group is optionally substituted with one or more instances of R7. In some embodiments, R6is a cyclopropyl group, optionally substituted with one or more instances of R7. In some embodiments, R6is a cyclopropyl group, optionally substituted with one instance of -CF3. In some embodiments, R6is selected from those depicted in the compounds of Table 1, below.

[0090] In some embodiments, R6is a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), optionally substituted with one or more instances of R7. In some embodiments, R6is tetrahydrofuranyl, optionally substituted with one or more instances of R7. In some embodiments, R6is tetrahydropyranyl, optionally substituted with one or more instances of R7. In some embodiments, R6is oxetanyl, optionally substituted with one or more instances of R7.

[0091] In some embodiments, R6is a 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), optionally substituted with one or more instances of R7. In some embodiments, R6is furanyl, optionally substituted with one or more instances of R7. In some embodiments, R6is pyrazolyl, optionally substituted with one or more instances of R7. In some embodiments, R6is oxazolyl, optionally substituted with one or more instances of R7.

[0092] As defined generally above, each instance of R7is independently halogen, –CN, –NO2, – OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, – C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, - N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, –N(R)S(O)2R, an optionally substituted C1-6aliphatic group, an optionally substituted C1-6aliphatic-Cy group, or Cy. In some embodiments, each instance of R7is independently halogen, -OR, -CN, an optionally substituted C1-6aliphatic group, an optionally substituted C1-6aliphatic-Cy group, or Cy. In some embodiments, each instance of R7is independently –F, methyl, ethyl, isopropyl, isobutyl, -CN, optionally substituted phenyl, optionally substituted benzyl, -CF3, -CH2OH, -CH2OCH3, - CH2CH2OCH3, -CH2CH2F, cyclopropyl or –CH2-(cyclopropyl). In some embodiments, each instance of R7is independently a C1-6aliphatic group. . In some embodiments, R7is -CF3.

[0093] In some embodiments, -L2-R6is a substituent of Table C: Table C: Exemplary -L2-R6substituents

[0094] In some embodiments, -L2-R6is In some emb2 6odiments, -L-R is In so2 6me embodiments, -L-R is

[0095] In some embodiments, -L2-R6is

[0096] In some embodiments, -L2-R6is

[0097] In some embodiments, -L2-R6is

[0098] As defined generally above, L3is a saturated or unsaturated, straight or branched, optionally substituted bivalent C1-4hydrocarbon chain, wherein 0-2 methylene units of L3are independently replaced by -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -C(S)-, - NRS(O)2-, -S(O)2NR-, -NRC(O)-, -C(O)NR-, -OC(O)NR-, -NRC(O)O-, or -NRC(O)NR-.

[0099] In some embodiments, L3is a saturated or unsaturated, straight or branched, optionally substituted bivalent C1-4hydrocarbon chain, wherein 0-2 methylene units of L3are independently replaced by -S(O)2-, -C(O)NR-, or -C(O)-. In some embodiments, L3is a C1-4alkylene chain, wherein 1-2 methylene units of L3are independently replaced by -S(O)2-, -C(O)NR-, or -C(O)-. In some embodiments, L3is C1-4alkylene chain, wherein 1 methylene unit of L3is replaced by - S(O)2-, -C(O)NR-, or -C(O)-. In some embodiments, L3is a saturated or unsaturated, straight or branched, optionally substituted bivalent C1-4alkylene chain, wherein 0-2 methylene units of L3are independently replaced by -C(O)O-, or -C(O)-. In some embodiments, L3is a C1-4alkylene chain, wherein 1-2 methylene units of L3are independently replaced by -C(O)O-, or -C(O)-. In some embodiments, L3is C1-4alkylene chain, wherein 1 methylene unit of L3is replaced by - C(O)O-, or -C(O)-. In some embodiments, L3is a saturated optionally substituted bivalent C1-4hydrocarbon chain. In some embodiments, L3is a saturated bivalent C1-4 hydrocarbon chain, substituted on a single methylene unit by two substituents, which together with the intervening carbon atom form a 3-7 membered carbocyclic ring or heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, L3is, In some embodiments, L3is,In some embodiments, L3isIn some embodiments, L3is In some embodiment3 3s, L isIn some embodiments, L is selected from those depicted in the compounds of Table 1, below.

[0100] As defined generally above, R8is a cyclic group selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and an 8-10 membered bicyclic heteroaromatic ring (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the cyclic group is optionally substituted with one or more instances of R9.

[0101] In some embodiments, R8is a cyclic group selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and an 8-10 membered bicyclic heteroaromatic ring (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the cyclic group is optionally substituted with one or more instances of R9. In some embodiments, R8is a cyclic group selected from a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, andsulfur), and an 8-10 membered bicyclic heteroaromatic ring (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the cyclic group is optionally substituted with one or more instances of R9. In some embodiments, R8is a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), optionally substituted with one or more instances of R9. In some embodiments, R8is a 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), optionally substituted with one or more instances of R9. In some embodiments, R8is an 8-10 membered bicyclic heteroaromatic ring (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur), optionally substituted with one or more instances of R9. In some embodiments, R8is a cyclic group selected from pyrazolyl, oxazolyl, thiazolyl, pyrrolidinyl, tetrahydropyranyl, pyridinyl, imidazolyl, indolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, piperidinyl, pyrazinyl, and indazolyl, wherein the cyclic group is optionally substituted with one or more instances of R9. In some embodiments, R8is a pyrazolyl or thiazolyl group, optionally substituted with one or more instances of R9. In some embodiments, R8is a pyrazolyl or thiazolyl group. In some embodiments, R8is selected from those depicted in the compounds of Table 1, below.

[0102] As defined generally above, each instance of R9is independently halogen, –CN, –NO2, – OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, – C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, - N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, –N(R)S(O)2R, an optionally substituted C1-6aliphatic group, an optionally substituted C1-6aliphatic-Cy group, or Cy.

[0103] In some embodiments, each instance of R9is independently halogen, an optionally substituted C1-6aliphatic group, an optionally substituted C1-6aliphatic-Cy group, or Cy. In some embodiments, each instance of R9is independently an optionally substituted C1-6aliphatic-Cy group, wherein the Cy is an optionally substituted group selected from phenyl, cyclohexyl, pyridinyl, piperidinyl, cyclopropyl, or tetrahydropyranyl. In some embodiments, R9is a benzylic group. In some embodiments, each instance of R9is independently halogen or an optionally substituted C1-6aliphatic group. In some embodiments, R9is selected from those depicted in the compounds of Table 1, below.

[0104] In some embodiments, -L3-R8is a substituent of Table D: Table D: Exemplary -L3-R8substituents

[0105] In some embodiments, -L3-R8is In some embodiments, -L3-R8is

[0106] In some embodiments, -L3-R8is

[0107] In some embodiments, -L3-R8is

[0108] In some embodiments, the compound of Formula IA is a compound of Formula IIA:or a pharmaceutically acceptable salt thereof, wherein RA, RB, L2, R6, L3and R8, and their constituent groups, are each as defined and described herein. In some embodiments, RA, RB, L2, R6, L3and R8, and their constituent groups, are each as defined and described in Formula IA. In some embodiments, RAis a substituent from Table B. In some embodiments, -L2-R6is a substituent from Table C. In some embodiments, -L3-R8is a substituent from Table D. In some embodiments, RAis a substituent from Table B, and -L2-R6is a substituent from Table C. In some embodiments, RAis a substituent from Table B, and -L3-R8is a substituent from Table D. In some embodiments, -L2-R6is a substituent from Table C, and -L3-R8is a substituent from Table D. And in some embodiments, RAis a substituent from Table B, -L2-R6is a substituent from Table C, and -L3-R8is a substituent from Table D.

[0109] In some embodiments, the compound of Formula IA is a compound of Formula IIB:or a pharmaceutically acceptable salt thereof, wherein RA, RB, L2, R6, L3and R8, and their constituent groups, are each as defined and described herein. In some embodiments, RA, RB, L2, R6, L3and R8, and their constituent groups, are each as defined and described in Formula IA. In some embodiments, RAis a substituent from Table B. In some embodiments, -L2-R6is a substituent from Table C. In some embodiments, -L3-R8is a substituent from Table D. In some embodiments, RAis a substituent from Table B, and -L2-R6is a substituent from Table C. In some embodiments, RAis a substituent from Table B, and -L3-R8is a substituent from Table D. In some embodiments, -L2-R6is a substituent from Table C, and -L3-R8is a substituent from Table D. In some embodiments, RAis a substituent from Table B, -L2-R6is a substituent from Table C, and -L3-R8is a substituent from Table D.

[0110] In some embodiments, the compound of Formula I or IA is a compound of Formula II:or a pharmaceutically acceptable salt thereof, wherein RA, L2, R6, L3and R8, and their constituent groups, are each as defined and described herein. In some embodiments, RA, L2, R6, L3and R8, and their constituent groups, are each as defined and described in Formula IA. In some embodiments, RAis a substituent from Table B. In some embodiments, -L2-R6is a substituent from Table C. In some embodiments, -L3-R8is a substituent from Table D. In some embodiments, RAis a substituent from Table B, and -L2-R6is a substituent from Table C. In some embodiments, RAis a substituent from Table B, and -L3-R8is a substituent from Table D. In some embodiments, -L2-R6is a substituent from Table C, and -L3-R8is a substituent from Table D. And in some embodiments, RAis a substituent from Table B, -L2-R6is a substituent from Table C, and -L3-R8is a substituent from Table D.

[0111] In some embodiments, the compound of Formula I or IA is a compound of Formula IIIa:or a pharmaceutically acceptable salt thereof, wherein L1, R1, R2, R3, L2, R6, L3and R8, and their constituent groups, are each as defined and described herein. In some embodiments, R1is phenyl. In some embodiments, R1is cyclohexyl. In some embodiments, R1is. In some embodiments, R1is. In some embodiments, R1isIn some embodiments, R1isIn some embodiments, R1is -CF3. In some embodiments, R2is a substituent from Table A. In some embodiments, R2is –C(O)NR2, wherein the two R groups of –C(O)NR2,taken together with the intervening nitrogen atom, form a cyclic group selected from an optionally substituted 4-7 membered saturated ring (having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur), and a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring that is optionally bridged bicyclic or spirocyclic (having 1-4 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur) wherein the cyclic group is optionally substituted with one or more instances of R9, wherein R9is selected from –CN, -C(O)O(C1-4alkyl), –O(C1-4alkyl), C1-4haloalkyl, halo, an optionally substituted C1-6aliphatic group, an optionally substituted cyclic group selected from phenyl, a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and a 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); and R3is hydrogen. In some embodiments, L2is a methylene. In some embodiments, L3is a methylene. In some embodiments, both L2and L3are methylene. In some embodiments, L2is a -C(O)-. In some embodiments, L3is a -C(O)-. In some embodiments, both L2and L3are -C(O)-. In some embodiments, RAis a substituent of Table B. In some embodiments, -L2-R6is In some embodiments, -2 6 2L -R isIn some embodiments, -L - R6is a substituent of Table C. In some embodiments, -L3-R8is a substituent from Table D. In some embodiments, -L3-R8iswherein R9is -CF3, -CN, -C(O)OH, - C(O)OCH3, -C(O)OCH2CH3, -C(O)OC(CH3)3, or -C(O)OCH2CH2CH3.

[0112] In some embodiments, the compound of Formula I or IA is a compound of Formula IIIb:or a pharmaceutically acceptable salt thereof, wherein R4, R5, L2, R6, L3and R8, and their constituent groups, are each as defined and described herein. In some embodiments, L2is a methylene. In some embodiments, L3is a methylene. In some embodiments, both L2and L3are methylene. In some embodiments, L2is -C(O)-. In some embodiments, L3is -C(O)-. In some embodiments, both L2and L3are -C(O)-. In some embodiments, -L2-R6is a substituent from Table C. In some embodiments, -L2-R6is. In some embodiments, -L2-R6is Insome embodiments, -L3-R8is a substituent from Table D. In some embodiments, -L3-R8isIn some embodiments, R4and R5, together, with the nitrogen to which they are attached, form an optionally substituted piperazine or an optionally substituted piperidine.

[0113] In some embodiments, the compound of Formula I or IA is a compound of Formula IVa:or a pharmaceutically acceptable salt thereof, wherein RA, L2, R6, and R8, and their constituent groups, are each as defined and described herein. In some embodiments, RAis a substituent from Table B. In some embodiments, RAis2wherein R is –C(O)NR2, wherein the two R groups of –C(O)NR2, taken together with the intervening nitrogen atom, form a cyclic group selected from a 4-7 membered saturated heterocyclic ring (having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur), and a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring that is optionally bridged bicyclic or spirocyclic (having 1-4 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur) wherein the cyclic group is optionally substituted with one or moreinstances of R9, wherein R9is selected from –CN, -C(O)O(C1-3alkyl), –O(C1-3alkyl), C1-3haloalkyl, halo, optionally substituted C1-6aliphatic group, an optionally substituted cyclic group selected phenyl, a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and a 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); and R3is hydrogen. In some embodiments, -L2-R6is a substituent from Table C. In some embodiments, -L2-R6is In some embodiments, -L2-6R isIn some embodiments, -L3-R8is wh9erein R is -CF3, -CN, -C(O)OH, - C(O)OCH3, -C(O)OCH2CH3, -C(O)OC(CH3)3, or -C(O)OCH2CH2CH3. In some embodiments, R8iswherein R9is methyl. In some embodiments, R8is

[0114] In some embodiments, the compound of Formula I is a compound of Formula IVb:or a pharmaceutically acceptable salt thereof, wherein RA, L2, R6, and R9, and their constituent groups, are each as defined and described herein. In some embodiments, the thiazolyl group is not substituted with R9. In some embodiments, RAis a substituent from Table B. In some embodiments, -L2-R6is a substituent from Table C. In some embodiments, -L2-R6is. In some embodiments, -L2-R6is

[0115] In some embodiments, the compound of Formula I or IA is a compound of Formula IVc:or a pharmaceutically acceptable salt thereof, wherein RA, L2, R6, and R9, and their constituent groups, are each as defined and described herein. In some embodiments, the pyrazolyl group is not substituted with R9. In some embodiments, the pyrazolyl group is substituted with one instance of R9, wherein R9is an optionally substituted benzyl group. In some embodiments, RAis a substituent from Table B. In some embodiments, -L2-R6is a substituent from Table C. In some embodiments, -L2-R6is2 6In some embodiments, -L -R is

[0116] In some embodiments, the compound of Formula I or IA is a compound of Formula Va:or a pharmaceutically acceptable salt thereof, wherein RA, R6, L3and R8, and their constituent groups, are each as defined and described herein. In some embodiments, R6is an optionally substituted cyclopropyl group. In some embodiments, RAis a substituent from Table B. In some embodiments, -L3-R8is a substituent from Table D. In some embodiments, -L3-R8iswherein R9is -CF3, -CN, -C(O)OH, -C(O)OCH3, -C(O)OCH2CH3, -C(O)OC(CH3)3, or -C(O)OCH2CH2CH3.

[0117] In some embodiments, the compound of Formula I or IA is a compound of Formula Vb:or a pharmaceutically acceptable salt thereof, wherein RA, R6, and R8, and their constituent groups, are each as defined and described herein. In some embodiments, R6is an optionally substituted cyclopropyl group. In some embodiments, RAis a substituent from Table B. In some embodiments, R6is8. In some embodiments, R iswherein R9is -CF3, -CN, -C(O)OH, -C(O)OCH3, -C(O)OCH2CH3, -C(O)OC(CH3)3, or - C(O)OCH2CH2CH3. In some embodiments, R8is9wherein R is methyl. In some embodiments, R8is

[0118] In some embodiments, the compound of Formula I or IA is a compound of Formula VIa:or a pharmaceutically acceptable salt thereof, wherein L1, R1, R2, R3, R6, and R8, and their constituent groups, are each as defined and described herein. In some embodiments, L1is wherein the on t1 6he left connects to R . In some embodiments, R is an optionally substituted cyclopropyl group. In some embodiments, L1iswherein theon the left connects to R1, wherein R1is . In some embodiments,1R is phenyl. In some embodiments, R1is cyclohexyl. In some embodiments, R1is. In some embodiments, R1is. In some embodiments, R1is .In some embodiments, R1is In some embodiments, R1is -CF . In s23ome embodiments, R is a substituent from Table A. In some embodiments, R2is –C(O)NR2, wherein the two R groups, taken together with the intervening nitrogen atom, form an optionally substituted 4-7 membered saturated ring (having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur), and R3is hydrogen. In some embodiments, R2is –C(O)NR2, wherein the two R groups of –C(O)NR2, taken together with the intervening nitrogen atom, form a cyclic group selected from an optionally substituted 4-7 membered saturated ring (having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur), and a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring that is optionally bridged bicyclic or spirocyclic (having 1-4 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur) wherein the cyclic group is optionally substituted withone or more instances of R9, wherein R9is selected from –CN, -C(O)O(C1-3alkyl), –O(C1-3alkyl), C1-3haloalkyl, halo, an optionally substituted C1-6aliphatic group, an optionally substituted cyclic group selected from phenyl, a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and a 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); and R3is hydrogen. In some embodiments, R6is an optionally substituted cyclopropyl group. In some embodiments, R6is In some embodiments, R8is wherein R9is -CF3,-CN, -C(O)OH, -C(O)OCH3, -C(O)OCH2CH3, -C(O)OC(CH3)3, or -C(O)OCH2CH2CH3. In some embodiments, R8is wherein R9is methyl.8In some embodiments, R is

[0119] In some embodiments, the compound of Formula I or IA is a compound of Formula VIb:or a pharmaceutically acceptable salt thereof, wherein L1, R1, R2, R3, R6, and R9, and their constituent groups, are each as defined and described herein. In some embodiments, R1is phenyl. In some embodiments, R1is cyclohexyl. In some embodiments, R1isIn some embodiments, R1is In some embodime1 1nts, R is -CF3. In some embodiments, L is an optionally substituted straight or branched C1-4alkylene chain, wherein 1-2 methylene units of L1are independently replaced by -O-, -NR-, -C(O)O-, or -NRC(O)-. In some embodiments, L1is, wherein the on the left connects to R1. In some embodime1nts, L is wherein theon the left connects to R1, wherein R1isInsome embodiments, R2is a substituent from Table A. In some embodiments, R2is –C(O)NR2, wherein the two R groups, taken together with the intervening nitrogen atom, form an optionally substituted 4-7 membered saturated ring (having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur), and R3is hydrogen. In some embodiments, the thiazolyl group is not substituted with R9. In some embodiments, R2is – C(O)NR2, wherein the two R groups, –C(O)NR2, taken together with the intervening nitrogen atom, form a cyclic group selected from an optionally substituted 4-7 membered saturated ring (having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur), and a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring that is optionally bridged bicyclic or spirocyclic (having 1-4 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur) wherein the cyclic group is optionally substituted with one or more instances of R9, wherein R9is selected from – CN, -C(O)O(C1-3alkyl), –O(C1-3alkyl), C1-3haloalkyl, halo, optionally substituted C1-6aliphatic group, an optionally substituted cyclic group selected from phenyl, a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and a 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); and R3is hydrogen. In some embodiments, R6is an optionally substituted cyclopropyl group. In some embodiments, R6is

[0120] In some embodiments, the compound of Formula I or IA is a compound of Formula VIc:or a pharmaceutically acceptable salt thereof, wherein L1, R1, R2, R3, R6, and R9, and their constituent groups, are each as defined and described herein. In some embodiments, R1is phenyl. In some embodiments, R1isIn some embodiments, R1is cyclohexyl. In some embodiments, L1is an optionally substituted straight or branched C1-4alkylene chain, wherein 1-2 methylene units of L1are independently replaced by -O-, -NR-, -C(O)O-, or -NRC(O)-. In some embodiments, L1is, wherein the1on the left connects to R . In some embodiments, L1is wherein the1 1on the left connects to R , wherein R is. In some embodiments, R2is a substituent from Table A. In some embodiments, R2is –C(O)NR2, wherein the two R groups, taken together with the intervening nitrogen atom, form an optionally substituted 4-7 membered saturated ring (having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur), and R3is hydrogen. In some embodiments, the pyrazolyl group is not substituted with R9. In some embodiments, the pyrazolyl group is substituted with one instance of R9, wherein R9is a benzyl group. In some embodiments, R2is –C(O)NR2, wherein the two R groups of –C(O)NR2, taken together with the intervening nitrogen atom, form a cyclic group selected from an optionally substituted 4-7 membered saturated ring (having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur), and a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring that is optionally bridged bicyclic or spirocyclic (having 1-4 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur) wherein the cyclic group is optionally substituted with one or more instances of R9, wherein R9is selected from – CN, -C(O)O(C1-3alkyl), –O(C1-3alkyl), C1-3haloalkyl, halo, an optionally substituted C1-6aliphaticgroup, an optionally substituted cyclic group selected from phenyl, a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and a 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); and R3is hydrogen. In some embodiments, R6is an optionally substituted cyclopropyl group. In some embodiments, R6is

[0121] In some embodiments, the compound of Formula I or IA is a compound of Formula VId:or a pharmaceutically acceptable salt thereof, wherein R4, R5, R6, and R8, and their constituent groups, are each as defined and described herein. In some embodiments, R6is an optionally substituted cyclopropyl group. In some embodiments, R6isIn some embodiments, R8iswherein R9is -CF3, -CN, -C(O)OH, -C(O)OCH3, - C(O)OCH2CH3, -C(O)OC(CH3)3, or -C(O)OCH2CH2CH3.In some embodiments, R8iswherein R9is methyl. In some embodiments, R8isIn some embodiments, R4and R5, together, with the nitrogen to which they are attached, form an optionally substituted piperazine or an optionally substituted piperidine.

[0122] In some embodiments, the compound of Formula I or IA is a compound of Formula VIe:or a pharmaceutically acceptable salt thereof, wherein R4, R5, R6, and R9, and their constituent groups, are each as defined and described herein. In some embodiments, R6is an optionally substituted cyclopropyl group. In some embodiments, R6isIn some embodiments, R9is methyl. In some embodiments, the thiazolyl group is not substituted with R9. In some embodiments, R4and R5, together, with the nitrogen to which they are attached, form an optionally substituted piperazine or an optionally substituted piperidine.

[0123] In some embodiments, the compound of Formula I or IA is a compound of Formula VIf:or a pharmaceutically acceptable salt thereof, wherein R4, R5, R6, and R9, and their constituent groups, are each as defined and described herein. In some embodiments, R6is an optionally substituted cyclopropyl group. In some embodiments, the pyrazolyl group is not substituted with R9. In some embodiments, R6is. In some embodiments, the pyrazolyl group is substituted with one instance of R9, wherein R9is a benzyl group. In some embodiments, the pyrazolyl group is substituted with one instance of R9, wherein R9is a benzyl group substituted with CF3, -CN, -C(O)OH, -C(O)OCH3, -C(O)OCH2CH3, -C(O)OC(CH3)3, or -C(O)OCH2CH2CH3..In some embodiments, R4and R5, together, with the nitrogen to which they are attached, form an optionally substituted piperazine or an optionally substituted piperidine.

[0124] In some embodiments, the compound of Formula I or IA is a compound of Formula VIIa:or a pharmaceutically acceptable salt thereof, wherein L1, R1, R2, R6, and R8, and their constituent groups, are each as defined and described herein. In some embodiments, R1is phenyl. In some embodiments, R1is1In some embodiments, R isIn some embodiments, R1is -CF3. In some embodiments, L1is an optionally substituted straight or branched C1-4alkylene chain, wherein 1-2 methylene units of L1are independently replaced by - O-, -NR-, -C(O)O-, or -NRC(O)-. In some embodiments, L1is, wherein theon the left connects to R1. In some embodiments, L1is, wherein theon the left connects to R1, wherein R1is. In some embodiments, the two R groups taken together with the intervening nitrogen atom, form a cyclic group selected from an optionally substituted 4-7 membered saturated ring (having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur), and a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring that is optionally bridged bicyclic or spirocyclic (having 1-4 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur) wherein the cyclic group is optionally substituted with one or more instances of R9, wherein R9is selected from –CN, -C(O)O(C1-3alkyl), –O(C1-3alkyl), C1-3haloalkyl, halo, an optionally substituted C1-6aliphatic group, an optionally substituted cyclic group selected fromphenyl, a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and a 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); and R3is hydrogen. In some embodiments, R8iswherein R9is -CF3, -CN, -C(O)OH, -C(O)OCH3, -C(O)OCH2CH3, -C(O)OC(CH3)3, or - C(O)OCH2CH2CH3. In some embodiments, R8iswherein R9is methyl. In some embodiments, R8isIn some embodiments, R6is an optionally substituted cyclopropyl group. In some embodiments, R6is.

[0125] In some embodiments, the compound of Formula I or IA is a compound of Formula VIIb:or a pharmaceutically acceptable salt thereof, wherein L1, R1, R2, R6, and R9, and their constituent groups, are each as defined and described herein. In some embodiments, R1is phenyl. In some embodiments, R1is cyclohexyl. In some embodiments, R1isIn some embodiments, R1is. In some embodiments, R1is -CF3. In some embodiments, L1is an optionally substituted straight or branched C1-4alkylene chain, wherein 1-2 methylene units of L1areindependently replaced by -O-, -NR-, -C(O)O-, or -NRC(O)-. In some embodiments, L1is wherein the on th1 6e left connects to R . In some embodiments, R is an optionally substituted cyclopropyl group. In some embodiments, L1is, wherein theon the left connects to R1, wherein R1isIn some embodiments, the two R groups taken together with the intervening nitrogen atom, form a cyclic group selected from an optionally substituted 4-7 membered saturated ring (having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur), and a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring that is optionally bridged bicyclic or spirocyclic (having 1-4 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur) wherein the cyclic group is optionally substituted with one or more instances of R9, wherein R9is selected from –CN, -C(O)O(C1-3alkyl), –O(C1-3alkyl), C1-3haloalkyl, halo, optionally substituted C1-6aliphatic group, an optionally substituted cyclic group selected from phenyl, a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and a 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); and R3is hydrogen. In some embodiments, R6is an optionally substituted cyclopropyl group. In some embodiments, R6is. In some embodiments, the thiazolyl group is not substituted with R9.

[0126] In some embodiments, the compound of Formula I or IA is a compound of Formula VIIc:or a pharmaceutically acceptable salt thereof, wherein L1, R1, R2, R6, and R9, and their constituent groups, are each as defined and described herein. In some embodiments, R1is phenyl. In some embodiments, R1is cyclohexyl. In some embodiments, R1is. In some embodiments, R1is. In some embodiments, R1is -CF3. In some embodiments, L1is an optionally substituted straight or branched C1-4alkylene chain, wherein 1-2 methylene units of L1are independently replaced by -O-, -NR-, -C(O)O-, or -NRC(O)-. In some embodiments, L1is wherein the on the left connects to R1. In s1ome embodiments, L is, wherein the on the left connects to R1, wherein R1isIn some embodiments, the two R groups taken together with the intervening nitrogen atom, form a cyclic group selected from an optionally substituted 4-7 membered saturated ring (having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur), and a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring that is optionally bridged bicyclic or spirocyclic (having 1-4 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur) wherein the cyclic group is optionally substituted with one or more instances of R9, wherein R9is selected from –CN, -C(O)O(C1-3alkyl), –O(C1-3alkyl), C1-3haloalkyl, halo, optionally substituted C1-6aliphatic group, an optionally substituted cyclic group selected from phenyl, a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and a 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); and R3is hydrogen. In some embodiments, R6is an optionally substituted cyclopropyl group. In some embodiments, R6is . In some embodiments, the pyr9azolyl group is not substituted with R . In some embodiments, the pyrazolyl group is substituted with one instance of R9, wherein R9is a benzyl group. In some embodiments, the pyrazolyl group is substituted with one instance of R9, wherein R9is a benzyl group substituted with CF3, -CN, -C(O)OH, -C(O)OCH3, -C(O)OCH2CH3, -C(O)OC(CH3)3, or -C(O)OCH2CH2CH3..

[0127] In some embodiments, the compound of Formula I or IA is a compound of Formula VIIIa:or a pharmaceutically acceptable salt thereof, wherein L1, R1, R6, and R8, and their constituent groups, are each as defined and described herein, and cyclic moiety Z is an optionally substituted cyclic group formed from two R groups, as defined and described herein. In some embodiments, R1is phenyl. In some embodiments, R1is cyclohexyl. In some embodiments, R1is. In some embodiments, L1is an optionally substituted straight or branched C1-4alkylene chain, wherein 1-2 methylene units of L1are independently replaced by -O-, -NR-, -C(O)O-, or -NRC(O)- . In some embodiments, L1is, wherein theon the left connects to R1. In some embodiments, L1is wherein the on the left co1 1nnects to R , wherein R isIn some embodiments, R1i1sIn some embodiments, R is -CF3. In some embodiments, cyclic moiety Z with the intervening nitrogen atom, forms a cyclic group selected from an optionally substituted 4-7 membered saturated ring (having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur), and a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring that is optionally bridged bicyclic or spirocyclic (having 1-4 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur) wherein the cyclic group is optionally substituted with one or more instances of R9, wherein R9is selected from –CN, -C(O)O(C1-3alkyl), –O(C1-3alkyl), C1-3haloalkyl, halo, an optionally substituted C1-6aliphatic group, an optionally substituted cyclicgroup selected from phenyl, a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and a 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); and R3is hydrogen. In some embodiments, R8iswherein R9is -CF3, -CN, -C(O)OH, -C(O)OCH3, - C(O)OCH2CH3, -C(O)OC(CH3)3, or -C(O)OCH2CH2CH3. In some embodiments, R8is wherein R9is methyl. In som8e embodiments, R isIn some embodiments, R6isIn some embodiments, R6is an optionally substituted cyclopropyl group. In some embodiments, or in any of the aforementioned embodiments of this paragraph, Z is an optionally substituted cyclic group selected from piperidinyl, morpholinyl, piperazinyl, azetindinyl, pyrrolidinyl, azaspiro[3.3]heptanyl, and diazaspiro[3.3]heptanyl. In some embodiments, or in any of the aforementioned embodiments of this paragraph, Z is piperidinyl or piperazinyl substituted with one instance of R9wherein the R9is an optionally substituted benzyl or an optionally substituted cyclic group selected from phenyl and 5-6 membered heteroaryl.

[0128] In some embodiments, the compound of Formula I or IA is a compound of Formula VIIIb:or a pharmaceutically acceptable salt thereof, wherein L1, R1, and R9, and their constituent groups, are each as defined and described herein, and cyclic moiety Z is an optionally substituted cyclic group formed from two R groups, as defined and described herein. In some embodiments, R1is phenyl. In some embodiments, R1is. In some embodiments, R1issome embodiments, R1is -CF3. In some embodiments, R1is cyclohexyl. In some embodiments, L1is an optionally substituted straight or branched C1-4alkylene chain, wherein 1-2 methylene units of L1are independently replaced by -O-, -NR-, -C(O)O-, or -NRC(O)-. In some embodiments, L1is, wherein theon the left connects to R1. In some embodiments, L1is wherein the on the left conne1 1cts to R , wherein R is. In some embodiments, the cyclic moiety Z taken together with the intervening nitrogen atom, forms a cyclic group selected from an optionally substituted 4-7 membered saturated ring (having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur), and a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring that is optionally bridged bicyclic or spirocyclic (having 1-4 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur) wherein the cyclic group is optionally substituted with one or more instances of R9, wherein R9is selected from –CN, -C(O)O(C1-3alkyl), –O(C1-3alkyl), C1-3haloalkyl, halo, an optionally substituted C1-6aliphatic group, an optionally substituted cyclic group selected from phenyl, a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and a 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); and R3is hydrogen. In some embodiments, R6is an optionally substituted cyclopropyl group. In some embodiments, R6is In some embodiments, the thiazolyl gr9oup is not substituted with R . In some embodiments, the thiazolyl group is substituted with 0-1 R9instances which are methyl. In some embodiments, Z, or in any of the aforementioned embodiments of this paragraph, is an optionally substituted cyclic group selected from piperidinyl, morpholinyl, piperazinyl, azetindinyl, pyrrolidinyl, azaspiro[3.3]heptanyl, and diazaspiro[3.3]heptanyl. In some embodiments, or in anyof the aforementioned embodiments of this paragraph, Z is piperidinyl or piperazinyl substituted with one instance of R9wherein the R9is an optionally substituted benzyl or an optionally substituted cyclic group selected from phenyl and 5-6 membered heteroaryl.

[0129] In some embodiments, the compound of Formula I or IA is a compound of Formula VIIIc:or a pharmaceutically acceptable salt thereof, wherein L1, R1, R6, and R9, and their constituent groups, are each as defined and described herein, and cyclic moiety Z is an optionally substituted cyclic group formed from two R groups, as defined and described herein. In some embodiments, R1is phenyl. In some embodiments, R1is cyclohexyl. In some embodiments, R1is. In some embodiments, L1is an optionally substituted straight or branched C1-4alkylene chain, wherein 1-2 methylene units of L1are independently replaced by -O-, -NR-, -C(O)O-, or -NRC(O)- . In some embodiments, L1is, wherein theon the left connects to R1. In some embodiments, L1is, wherein theon the left connects to R1, wherein R1is In some embodiments, R1is In some em1bodiments, R is -CF3. In some embodiments, the cyclic moiety Z taken together with the intervening nitrogen atom, forms a cyclic group selected from an optionally substituted 4-7 membered saturated ring (having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur), and a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring that is optionally bridged bicyclic or spirocyclic (having 1-4 heteroatoms, in addition to thenitrogen, independently selected from nitrogen, oxygen, and sulfur) wherein the cyclic group is optionally substituted with one or more instances of R9, wherein R9is selected from – CN, -C(O)O(C1-3alkyl), –O(C1-3alkyl), C1-3haloalkyl, halo, an optionally substituted C1-6aliphatic group, an optionally substituted cyclic group selected from phenyl, a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and a 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); and R3is hydrogen. In some embodiments, R6is an optionally substituted cyclopropyl group. In some embodiments, R6is In so9me embodiments, the pyrazolyl group is not substituted with R . In some embodiments, the pyrazolyl group is substituted with one instance of R9, wherein R9is a benzyl group. In some embodiments, the pyrazolyl group is substituted with one instance of R9, wherein R9is a benzyl group substituted with CF3, -CN, -C(O)OH, -C(O)OCH3, -C(O)OCH2CH3, or -C(O)OCH2CH2CH3..In some embodiments, or in any of the aforementioned embodiments of this paragraph, Z is an optionally substituted cyclic group selected from piperidinyl, morpholinyl, piperazinyl, azetindinyl, pyrrolidinyl, azaspiro[3.3]heptanyl, and diazaspiro[3.3]heptanyl. In some embodiments, or in any of the aforementioned embodiments of this paragraph, Z is piperidinyl or piperazinyl substituted with one instance of R9wherein the R9is an optionally substituted benzyl or an optionally substituted cyclic group selected from phenyl and 5-6 membered heteroaryl.

[0130] In some embodiments, the compound of Formula I or IA is a compound of Formula IXa:or a pharmaceutically acceptable salt thereof, wherein R1and R8, and their constituent groups, are each as defined and described herein, and cyclic moiety Z is an optionally substituted cyclic group formed from two R groups, as defined and described herein. In some embodiments, R1is phenyl.In some embodiments, R1is. In some embodiments, R1isIn some embodiments, R1is. In some embodiments, R1is cyclohexyl. In some embodiments, R1is In some embodiments, R1is -CF . In some embodi83ments, R iswherein R9is -CF3, -CN, -C(O)OH, -C(O)OCH3, -C(O)OCH2CH3, - C(O)OC(CH3)3, or -C(O)OCH2CH2CH3. In some embodiments, R8is9wherein R is methyl. In some embodiments, R8isIn some embodiments, or in any of the aforementioned embodiments of this paragraph, Z is an optionally substituted cyclic group selected from piperidinyl, morpholinyl, piperazinyl, azetindinyl, pyrrolidinyl, azaspiro[3.3]heptanyl, and diazaspiro[3.3]heptanyl. In some embodiments, or in any of the aforementioned embodiments of this paragraph, Z is piperidinyl or piperazinyl substituted with one instance of R9wherein the R9is an optionally substituted benzyl or an optionally substituted cyclic group selected from phenyl and 5-6 membered heteroaryl.

[0131] In some embodiments, the compound of Formula I or IA is a compound of Formula IXa*:or a pharmaceutically acceptable salt thereof, wherein R1and R8, and their constituent groups, are each as defined and described herein, and cyclic moiety Z is an optionally substituted cyclic group formed from two R groups, as defined and described herein. In some embodiments, R1is phenyl. In some embodiments, R1is cyclohexyl. In some embodiments, R1is. In some embodiments, R1is. In some embodiments, R1is. In some embodiments, R1isIn some embodiments, R1is -CF3. In some embodiments, R8iswherein R9is -CF3, -CN, -C(O)OH, -C(O)OCH3, -C(O)OCH2CH3, - C(O)OC(CH3)3, or -C(O)OCH2CH2CH3. In some embodiments, R8is9wherein R is methyl. In some embodiments, R8isIn some embodiments, or in any of the aforementioned embodiments of this paragraph, Z is an optionally substituted cyclic group selected from piperidinyl, morpholinyl, piperazinyl, azetindinyl, pyrrolidinyl, azaspiro[3.3]heptanyl, and diazaspiro[3.3]heptanyl. In some embodiments, or in any of the aforementioned embodiments of this paragraph, Z is piperidinyl or piperazinyl substituted with one instance of R9wherein the R9is an optionally substituted benzyl or an optionally substituted cyclic group selected from phenyl and 5-6 membered heteroaryl.

[0132] In some embodiments, the compound of Formula I or IA is a compound of Formula IXa**:or a pharmaceutically acceptable salt thereof, wherein R1and R8, and their constituent groups, are each as defined and described herein, and cyclic moiety Z is an optionally substituted cyclic group formed from two R groups, as defined and described herein. In some embodiments, R1is phenyl. In some embodiments, R1is cyclohexyl. In some embodiments, R1is. In some embodiments, R1is. In some embodiments, R1is. In some embodiments, R1is In some embodiments, R1is -C8F3. In some embodiments, R iswherein R9is -CF3, -CN, -C(O)OH, -C(O)OCH3, -C(O)OCH2CH3, - C(O)OC(CH3)3, or -C(O)OCH2CH2CH3. In some embodiments, R8is9wherein R is methyl. In some embodiments, R8isIn some embodiments, or in any of the aforementioned embodiments of this paragraph, Z is an optionally substituted cyclic group selected from piperidinyl, morpholinyl, piperazinyl, azetindinyl, pyrrolidinyl, azaspiro[3.3]heptanyl, and diazaspiro[3.3]heptanyl. In some embodiments, or in any of the aforementioned embodiments of this paragraph, Z is piperidinyl or piperazinyl substituted withone instance of R9wherein the R9is an optionally substituted benzyl or an optionally substituted cyclic group selected from phenyl and 5-6 membered heteroaryl.

[0133] In some embodiments, the compound of Formula I or IA is a compound of Formula IXb:or a pharmaceutically acceptable salt thereof, wherein R1and R9, and their constituent groups, are each as defined and described herein, and cyclic moiety Z is an optionally substituted cyclic group formed from two R groups, as defined and described herein. In some embodiments, R1is phenyl. In some embodiments, R1is cyclohexyl. In some embodiments, R1is. In some embodiments, R1is. In some embodiments, R1is. In some embodiments, R1is. In some embodiments, R1is -CF3. In some embodiments, the thiazolyl group is not substituted with R9. In some embodiments, the thiazolyl group is substituted with one instance of R9, wherein R9is a benzyl group. In some embodiments, the thiazolyl group is substituted with one or two instances of R9, which are methyl groups. In some embodiments, or in any of the aforementioned embodiments of this paragraph, Z is an optionally substituted cyclic group selected from piperidinyl, morpholinyl, piperazinyl, azetindinyl, pyrrolidinyl, azaspiro[3.3]heptanyl, and diazaspiro[3.3]heptanyl. In some embodiments, or in any of the aforementioned embodiments of this paragraph, Z is piperidinyl or piperazinyl substituted with one instance of R9wherein the R9is an optionally substituted benzyl or an optionally substituted cyclic group selected from phenyl and 5-6 membered heteroaryl.

[0134] In some embodiments, the compound of Formula I or IA is a compound of Formula IXb*:or a pharmaceutically acceptable salt thereof, wherein R1and R9, and their constituent groups, are each as defined and described herein, and cyclic moiety Z is an optionally substituted cyclic group formed from two R groups, as defined and described herein. In some embodiments, R1is phenyl. In some embodiments, R1is cyclohexyl. In some embodiments, R1is. In some embodiments, R1is In some embodiments, R1is. In some embodiments,R1is1In some embodiments, R is -CF3. In some embodiments, the thiazolyl group is not substituted with R9. In some embodiments, the thiazolyl group is substituted with one instance of R9, wherein R9is a benzyl group. In some embodiments, the thiazolyl group is substituted with one or two instances of R9, which are methyl groups. In some embodiments, or in any of the aforementioned embodiments of this paragraph, Z is an optionally substituted cyclic group selected from piperidinyl, morpholinyl, piperazinyl, azetindinyl, pyrrolidinyl, azaspiro[3.3]heptanyl, and diazaspiro[3.3]heptanyl. In some embodiments, or in any of the aforementioned embodiments of this paragraph, Z is piperidinyl or piperazinyl substituted with one instance of R9wherein the R9is an optionally substituted benzyl or an optionally substituted cyclic group selected from phenyl and 5-6 membered heteroaryl.

[0135] In some embodiments, the compound of Formula I or IA is a compound of Formula IXb**:or a pharmaceutically acceptable salt thereof, wherein R1and R9, and their constituent groups, are each as defined and described herein, and cyclic moiety Z is an optionally substituted cyclic group formed from two R groups, as defined and described herein. In some embodiments, R1is phenyl. In some embodiments, R1is cyclohexyl. In some embodiments, R1is. In some embodiments, R1is In some emb1odiments, R is. In some embodiments, R1is. In some embodiments, R1is -CF3. In some embodiments, the thiazolyl group is not substituted with R9. In some embodiments, the thiazolyl group is substituted with one instance of R9, wherein R9is a benzyl group. In some embodiments, the thiazolyl group is substituted with one or two instances of R9, which are methyl groups. In some embodiments, or in any of the aforementioned embodiments of this paragraph, Z is an optionally substituted cyclic group selected from piperidinyl, morpholinyl, piperazinyl, azetindinyl, pyrrolidinyl, azaspiro[3.3]heptanyl, and diazaspiro[3.3]heptanyl. In some embodiments, or in any of the aforementioned embodiments of this paragraph, Z is piperidinyl or piperazinyl substituted with one instance of R9wherein the R9is an optionally substituted benzyl or an optionally substituted cyclic group selected from phenyl and 5-6 membered heteroaryl.

[0136] In some embodiments, the compound of Formula I or IA is a compound of Formula IXc:or a pharmaceutically acceptable salt thereof, wherein R1and R9, and their constituent groups, are each as defined and described herein, and cyclic moiety Z is an optionally substituted cyclic group formed from two R groups, as defined and described herein. In some embodiments, R1is phenyl. In some embodiments, R1is cyclohexyl. In some embodiments, R1is. In some embodiments, R1is In some embodiments,1R is. In some embodiments, R1is. In some embodiments, R1is -CF3. In some embodiments, the pyrazolyl group is not substituted with R9. In some embodiments, the pyrazolyl group is substituted with one instance of R9, wherein R9is a benzyl group. In some embodiments, or in any of the aforementioned embodiments of this paragraph, Z is an optionally substituted cyclic group selected from piperidinyl, morpholinyl, piperazinyl, azetindinyl, pyrrolidinyl, azaspiro[3.3]heptanyl, and diazaspiro[3.3]heptanyl. In some embodiments, or in any of the aforementioned embodiments of this paragraph, Z is piperidinyl or piperazinyl substituted with one instance of R9wherein the R9is an optionally substituted benzyl or an optionally substituted cyclic group selected from phenyl and 5-6 membered heteroaryl.

[0137] In some embodiments, the compound of Formula I or IA is a compound of Formula IXc*:or a pharmaceutically acceptable salt thereof, wherein R1and R9, and their constituent groups, are each as defined and described herein, and cyclic moiety Z is an optionally substituted cyclic group formed from two R groups, as defined and described herein. In some embodiments, R1is phenyl. In some embodiments, R1is cyclohexyl. In some embodiments, R1is. In some embodiments, R1is. In some embodiments, R1is. In some embodiments, R1is. In some embodiments, R1is -CF3. In some embodiments, the pyrazolyl group is not substituted with R9. In some embodiments, the pyrazolyl group is substituted with one instance of R9, wherein R9is a benzyl group. In some embodiments, the pyrazolyl group is substituted with one instance of R9, wherein R9is a benzyl group substituted with -CF3, -CN, - C(O)OH, -C(O)OCH3, -C(O)OCH2CH3, or -C(O)OCH2CH2CH3..In some embodiments, or in any of the aforementioned embodiments of this paragraph, Z is an optionally substituted cyclic group selected from piperidinyl, morpholinyl, piperazinyl, azetindinyl, pyrrolidinyl, azaspiro[3.3]heptanyl, and diazaspiro[3.3]heptanyl. In some embodiments, or in any of the aforementioned embodiments of this paragraph, Z is piperidinyl or piperazinyl substituted with one instance of R9wherein the R9is an optionally substituted benzyl or an optionally substituted cyclic group selected from phenyl and 5-6 membered heteroaryl.

[0138] In some embodiments, the compound of Formula I or IA is a compound of Formula IXc**:or a pharmaceutically acceptable salt thereof, wherein R1and R9, and their constituent groups, are each as defined and described herein, and cyclic moiety Z is an optionally substituted cyclic group formed from two R groups, as defined and described herein. In some embodiments, R1is phenyl. In some embodiments, R1is. In some embodiments, R1is. In some embodiments, R1is. In some embodiments, R1isIn some embodiments, R1is -CF3. In some embodiments, R1is cyclohexyl. In some embodiments, the pyrazolyl group is not substituted with R9. In some embodiments, the pyrazolyl group is substituted with one instance of R9, wherein R9is a benzyl group. In some embodiments, the pyrazolyl group is substituted with one instance of R9, wherein R9is a benzyl group substituted with -CF3, -CN, - C(O)OH, -C(O)OCH3, -C(O)OCH2CH3, or -C(O)OCH2CH2CH3..In some embodiments, or in any of the aforementioned embodiments of this paragraph, Z is an optionally substituted cyclic group selected from piperidinyl, morpholinyl, piperazinyl, azetindinyl, pyrrolidinyl, azaspiro[3.3]heptanyl, and diazaspiro[3.3]heptanyl. In some embodiments, or in any of the aforementioned embodiments of this paragraph, Z is piperidinyl or piperazinyl substituted with one instance of R9wherein the R9is an optionally substituted benzyl or an optionally substituted cyclic group selected from phenyl and 5-6 membered heteroaryl.

[0139] In some embodiments, the compound of Formula I or IA is a compound of Formula Xa:or a pharmaceutically acceptable salt thereof, wherein R1, R6, and R8, and their constituent groups, are each as defined and described herein. In some embodiments, R1is phenyl. In some embodiments, R1is cyclohexyl. In some embodiments, R1is. In some embodiments, R1isIn some embodiments, R1is In some embodiments, the two Rgroups taken together with the intervening nitrogen atom, form a cyclic group selected from an optionally substituted 4-7 membered saturated ring (having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur), and a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring that is optionally bridged bicyclic or spirocyclic (having 1-4 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur) wherein the cyclic group is optionally substituted with one or more instances of R9, wherein R9is selected from –CN, -C(O)O(C1-3alkyl), –O(C1-3alkyl), C1-3haloalkyl, halo, an optionally substituted C1-6aliphatic group, an optionally substituted cyclic group selected from phenyl, a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and a 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); and R3is hydrogen. In some embodiments, R6is an optionally substituted cyclopropyl group. In some embodiments, R6is8In some embodiments, R is wherein R9is -CF3, -CN, -C(O)OH, -C(O)OCH3, -C(O)OCH2CH3, -C(O)OC(CH3)3, or -C(O)OCH2CH2CH3. In some embodiments, R8iswherein R9is methyl. In some embodiments, R8is

[0140] In some embodiments, the compound of Formula I or IA is a compound of Formula Xb:or a pharmaceutically acceptable salt thereof, wherein R1, R6, and R8, and their constituent groups, are each as defined and described herein. In some embodiments, R1is phenyl. In some embodiments, R1is cyclohexyl. In some embodiments, R1is. In some embodiments, R1is In some embodiments, R1is6In some embodiments, R is an optionally substituted cyclopropyl group. In some embodiments, R6issome embodiments, R8iswherein R9is -CF3, -CN, -C(O)OH, - C(O)OCH3, -C(O)OCH2CH3, -C(O)OC(CH3)3, or -C(O)OCH2CH2CH3. In some embodiments, R8is9 8wherein R is methyl. In some embodiments, R is

[0141] In some embodiments, the compound of Formula I or IA is a compound of Formula Xc:or a pharmaceutically acceptable salt thereof, wherein Z, R1, R6, and R8, and their constituent groups, are each as defined and described herein. In some embodiments, R1is phenyl. In some embodiments, R1is cyclohexyl. In some embodiments, R1is. In some embodiments, R1is In some embodiments, R1is In s6ome embodiments, R is an optionally substituted cyclopropyl group. In some embodiments, R6issome embodiments, R8is9wherein R is -CF3, -CN, -C(O)OH, - C(O)OCH3, -C(O)OCH2CH3, -C(O)OC(CH3)3, or -C(O)OCH2CH2CH3. In some embodiments, R8is wherein R9is methyl. In som8e embodiments, R isIn some embodiments, or in any of the aforementioned embodiments of this paragraph, Z is an optionally substituted cyclic group selected from piperidinyl, morpholinyl, piperazinyl, azetindinyl, pyrrolidinyl, azaspiro[3.3]heptanyl, and diazaspiro[3.3]heptanyl. In some embodiments, or in any of the aforementioned embodiments of this paragraph, Z is piperidinyl or piperazinyl substituted with one instance of R9wherein the R9is an optionally substituted benzyl or an optionally substituted cyclic group selected from phenyl and 5-6 membered heteroaryl.

[0142] In some embodiments, the compound of Formula IA is a compound of Formula XIa:or a pharmaceutically acceptable salt thereof, wherein RB, R1, R6, and R8, and their constituent groups, are each as defined and described herein. In some embodiments, R1is phenyl. In some embodiments, R1is cyclohexyl. In some embodiments, R1is. In some embodiments, R1isIn some embodiments, R1isIn some embodiments, the two R groups taken together with the intervening nitrogen atom, form a cyclic group selected from an optionally substituted 4-7 membered saturated ring (having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur), and a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring that is optionally bridged bicyclic or spirocyclic (having 1-4 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur) wherein the cyclic group is optionally substituted with one or more instances of R9, wherein R9is selected from –CN, -C(O)O(C1-3alkyl), –O(C1-3alkyl), C1-3haloalkyl, halo, C1-6aliphatic group, an optionally substituted cyclic group selected from phenyl, a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and a 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); and R3is hydrogen. In some embodiments, R6is an optionally substituted cyclopropyl group. In some embodiments, R6is8In some embodiments, R iswherein R9is -CF3, -CN, -C(O)OH, -C(O)OCH3, -C(O)OCH2CH3, - C(O)OC(CH3)3, or -C(O)OCH2CH2CH3. In some embodiments, R8is9wherein R is methyl. In some embodiments, R8is

[0143] In some embodiments, the compound of Formula IA is a compound of Formula XIb:or a pharmaceutically acceptable salt thereof, wherein RB, R1, R6, and R8, and their constituent groups, are each as defined and described herein. In some embodiments, R1is phenyl. In some embodiments, R1is cyclohexyl. In some embodiments, R1is. In some embodiments, R1is In som1 6e embodiments, R isIn some embodiments, R is an optionally substituted cyclopropyl group. In some embodiments, R6isIn some embodiments, R8iswherein R9is -CF3, -CN, -C(O)OH, -C(O)OCH3, -C(O)OCH2CH3, -C(O)OC(CH3)3, or -C(O)OCH2CH2CH3. In some embodiments, R8iswherein R9is methyl. In some embodiments, R8is

[0144] In some embodiments, the compound of Formula IA is a compound of Formula XIc:or a pharmaceutically acceptable salt thereof, wherein Z, RB, R1, R6, and R8, and their constituent groups, are each as defined and described herein. In some embodiments, R1is phenyl. In some embodiments, R1is cyclohexyl. In some embodiments, R1is. In some embodiments, R1is In some embodiment1 6s, R isIn some embodiments, R is an optionally substituted cyclopropyl group. In some embodiments, R6issome embodiments, R8iswherein R9is -CF3, -CN, -C(O)OH, - C(O)OCH3, -C(O)OCH2CH3, -C(O)OC(CH3)3, or -C(O)OCH2CH2CH3. In some embodiments, R8is wh9 8erein R is methyl. In some embodiments, R isIn some embodiments, Z is an optionally substituted cyclic group selected from piperidinyl, morpholinyl, piperazinyl, azetindinyl, pyrrolidinyl, azaspiro[3.3]heptanyl, and diazaspiro[3.3]heptanyl. In someembodiments, or in any of the aforementioned embodiments of this paragraph, Z is piperidinyl or piperazinyl substituted with one instance of R9wherein the R9is an optionally substituted benzyl or an optionally substituted cyclic group selected from phenyl and 5-6 membered heteroaryl.

[0145] In some embodiments, the compound of Formula IA is a compound of Formula XIIa or XIIb:or a pharmaceutically acceptable salt thereof, wherein R1, R6, and R8, and their constituent groups, are each as defined and described herein, and whereinis -CH2-Cy or an optionally substituted cyclic group selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and an 8-10 membered bicyclic heteroaromatic ring (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R1is phenyl. In some embodiments, R1is cyclohexyl. In some embodiments, R1isIn some embodiments, R1is. In someembodiments, R1is. In some embodiments, R6is an optionally substituted cyclopropyl group. In some embodiments, R6is. In some embodiments, R8is wherein9R is -CF3, -CN, -C(O)OH, -C(O)OCH3, -C(O)OCH2CH3, - C(O)OC(CH3)3, or -C(O)OCH2CH2CH3. In some embodiments, R8is9wherein R is methyl. In some embodiments, R8is

[0146] In some embodiments, the compound of Formula IA is a compound of Formula XIIIa, XIIIb, XIIIc, or XIIId:or a pharmaceutically acceptable salt thereof, wherein R1, R6, and R8, and their constituent groups, are each as defined and described herein, and wherein R10has from 0 to 3 instances each independently selected from halogen, –CN, –NO2, –OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, –C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2,-N(R)S(O)2NR2, –N(R)S(O)2R, an optionally substituted C1-6aliphatic group, an optionally substituted C1-6aliphatic-Cy group, and Cy. In some embodiments, R10has from 0 to 3 instances each independently selected from -F, -CF3, -C(O)OH, -C(O)OCH3, -C(O)OCH2CH3, - C(O)OCH2CH2CH3, -C(O)OC(CH3)3, -OCH2C(O)OH, -OCH2C(O)OCH3, -CH3, - OC(CH3)2C(O)OH, -OC(CH3)2C(O)OCH3. In some embodiments, R1is cyclohexyl. In some embodiments, R1is1In some embodiments, R is. In some embodiments, R1isIn some embodiments, R6is an optionally substituted cyclopropyl group. In some embodiments, R6is In some8embodiments, R iswherein R9is -CF3, -CN, -C(O)OH, -C(O)OCH3, -C(O)OCH2CH3, - C(O)OC(CH3)3, or -C(O)OCH2CH2CH3. In some embodiments, R8is9wherein R is methyl. In some embodiments, R8is

[0147] In some embodiments, the compound of Formula IA is a compound of Formula XIV:or a pharmaceutically acceptable salt thereof, wherein R1, R6, and R8, and their constituent groups, are each as defined and described herein, and wherein R11is hydrogen, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, –C(O)NR2, -C(O)N(R)OR, an optionally substituted C1-6aliphatic group, an optionally substituted C1-6aliphatic-Cy group, or Cy. In some embodiments, R11is hydrogen, -C(O)OR, or an optionally substituted C1-6aliphatic group. In some embodiments, R1is cyclohexyl. In some embodiments, R1is. In some embodiments, R1is In s1 6ome embodiments, R isIn some embodiments, R is an optionally substituted cyclopropyl group. In some embodiments, R6issome embodiments, R8iswherein R9is -CF3, -CN, -C(O)OH, - C(O)OCH3, -C(O)OCH2CH3, -C(O)OC(CH3)3, or -C(O)OCH2CH2CH3. In some embodiments, R8is wherein R9is methyl. In some embodi8ments, R is

[0148] In some embodiments, at least one hydrogen atom of the compound is a deuterium atom. In some embodiments, at least one C1-C6aliphatic group of the compound is substituted with at least one deuterium atom. In some embodiments, at least one C1-C6alkyl group of the compound is substituted with at least one deuterium atom. In some embodiments, at least one C1-C6alkylene group of the compound is substituted with at least one deuterium atom. In some embodiments, at least one bivalent C1-6hydrocarbon chain group of the compound is substituted with at least one deuterium atom. In some embodiments, RBis –CD3. In some embodiments, R2is substituted with one or more deuterium atoms. In some embodiments, R1is substituted with one or more deuterium atoms.

[0149] Exemplary compounds of the present disclosure are set forth in Table 1, below.Table 1. Exemplary Compounds

[0150] In some embodiments, the present disclosure provides a compound set forth in Table 1, above, or a pharmaceutically acceptable salt thereof. In some embodiments, the disclosure provides a compound set forth in Table 1, above, or a pharmaceutically acceptable salt thereof, and any enantiomers, diastereomers, or conformation isomers thereof. The present disclosure contemplates any and all enantiomers, diastereomers and conformation isomers of a compound shown herein.

[0151] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier, excipient, vehicle, adjuvant or diluent. In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound set forth in Table 1 above, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier, excipient, vehicle, adjuvant or diluent. In some embodiments, the pharmaceutical composition further comprises an additional therapeutic agent.

[0152] Tn some embodiments, the present disclosure provides a complex comprising a CDK2 protein and a compound of the present disclosure.

[0153] In some embodiments, the present disclosure provides a method of inhibiting the activity of a cyclin-dependent kinase (CDK). In some embodiments, the method comprises contacting a compound of the present disclosure with a CDK. In some embodiments, the compound and the CDK are contacted in vivo. In some embodiments, the compound and the CDK are contacted in vitro. In some embodiments, the CDK is selected from CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK 10, CDK11, CDK 12 and CDK13. In some embodiments, the CDK is CDK2. In some embodiments, the CDK is CDK3. In some embodiments, the CDK is CDK4. Tn some embodiments, the CDK is CDK6. Tn some embodiments, the method inhibits the activity of both CDK2 and CDK3. In some embodiments, the method inhibits the activity of CDK2 and one or both of CDK4 and CDK6.

[0154] In some embodiments, the compounds of the present disclosure inhibit the activity of one or more CDKs selected from CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10, CDK11, CDK12 and CDK13. In some embodiments, the compounds of the present disclosure inhibit CDK2. In some embodiments, the compounds of the present disclosure inhibit CDK3. In some embodiments, the compounds of the present disclosure inhibit CDK4. In some embodiments, the compounds of the present disclosure inhibit CDK5. In some embodiments, the compounds of the present disclosure inhibit CDK6. In some embodiments, the compounds of the present disclosure are CDK2 / 3 inhibitors. In some embodiments, the compounds of the present disclosure are CDK2 / 4 / 6 inhibitors.

[0155] In some embodiments, the present disclosure provides compounds that selectively inhibit CDK2 over other cyclin-dependent kinases (CDKs). In some embodiments, the compounds of the present disclosure selectively inhibit CDK2 over one or more other CDKs, selected from CDK1, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10, CDK11, CDK12 and CDK13. In some embodiments, the compounds of the present disclosure selectively inhibit CDK2 over CDK4. In some embodiments, the compounds of the present disclosure selectively inhibit CDK2 over CDK6. Tn some embodiments, the compounds of the present disclosure selectively inhibit CDK2 over CDK4 and CDK6.

[0156] In some embodiments, the present disclosure provides compounds that selectively inhibit CDK2 / cyclin E complexes over other CDK complexes. 4. General Methods of Providing the Present Compounds

[0157] The compounds of this disclosure may be prepared or isolated in general by synthetic and / or semi-synthetic methods known to those skilled in the art for analogous compounds and by methods described in detail in the Examples, herein.

[0158] In the Schemes below, where a particular protecting group (“PG”), leaving group (“LG”), or transformation condition is depicted, one of ordinary skill in the art will appreciate that other protecting groups, leaving groups, and transformation conditions are also suitable and are contemplated. Such groups and transformations are described in detail in March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, M. B. Smith and J. March, 5thEdition, John Wiley & Sons, 2001, Comprehensive Organic Transformations, R. C. Larock, 2ndEdition, John Wiley & Sons, 1999, and Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999, the entirety of each of which is hereby incorporated herein by reference.

[0159] As used herein, the phrase “leaving group” (LG) includes, but is not limited to, halogens (e.g. fluoride, chloride, bromide, iodide), sulfonates (e.g. mesylate, tosylate, benzenesulfonate, brosylate, nosylate, triflate), diazonium, and the like.

[0160] Amino protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999, the entirety of which is incorporated herein by reference. Suitable amino protecting groups include, but are not limited to, aralkylamines, carbamates, cyclic imides, allyl amines, amides, and the like. Examples of such groups include t-butyloxycarbonyl (BOC), ethyloxycarbonyl, methyloxycarbonyl, trichloroethyloxycarbonyl, allyloxycarbonyl (Alloc), benzyloxocarbonyl (CBZ), allyl, phthalimide, benzyl (Bn), fluorenylmethylcarbonyl (Fmoc), formyl, acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, phenylacetyl, trifluoroacetyl, benzoyl, and the like.

[0161] Compounds of the present disclosure, including those of Formula I and the compounds of Table 1, can generally be prepared according the methods described below. Reagents andconditions can be modified and substituted using knowledge common to one of ordinary skill in the art, as needed, in order to arrive at the compounds of the present disclosure. Scheme 1: Synthesis of Spirocyclic Core StructureScheme 2: Racemic Functionalization of Spirocyclic Core StructureScheme 3: Synthesis of Individual Enantiomers via Separation of Intermediates usingOxazolidinone AuxiliaryScheme 4: Synthesis of Individual Enantiomers from Separated IntermediatesScheme 5: Synthesis of compounds having a threonine derivative RAgroup, with desired stereochemistry5. Uses, Formulation and Administration Pharmaceutically acceptable compositions

[0162] According to another embodiment, the disclosure provides a composition comprising a compound of this disclosure or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The amount of compound in compositions of this disclosure is such that it is effective to measurably inhibit a CDK2 protein, or a mutant thereof, in a biological sample or in a patient. In certain embodiments, the amount of compound in compositions of this disclosure is such that it is effective to measurably inhibit a CDK2 protein, or a mutant thereof, in a biological sample or in a patient. In certain embodiments, a composition of this disclosure is formulated for administration to a patient in need of suchcomposition. Tn some embodiments, a composition of this disclosure is formulated for oral administration to a patient.

[0163] Compositions of the present disclosure may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the compositions are administered subcutaneously, orally, intraperitoneally or intravenously. In some embodiments, the compositions are administered orally. In some embodiments, the compositions are administered intraperitoneally. In some embodiments, the compositions are administered intravenously. Tn some embodiments, the compositions are administered subcutaneously. Sterile injectable forms of the compositions of this disclosure may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3 -butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium.

[0164] For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.

[0165] Pharmaceutically acceptable compositions of this disclosure may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueoussuspensions or solutions. Tn the case of tablets for oral use, carriers commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.

[0166] Alternatively, pharmaceutically acceptable compositions of this disclosure may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.

[0167] Pharmaceutically acceptable compositions of this disclosure may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

[0168] Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used.

[0169] For topical applications, provided pharmaceutically acceptable compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of compounds of this disclosure include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, provided pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

[0170] For ophthalmic use, provided pharmaceutically acceptable compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, assolutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutically acceptable compositions may be formulated in an ointment such as petrolatum.

[0171] Pharmaceutically acceptable compositions of this disclosure may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0172] Most preferably, pharmaceutically acceptable compositions of this disclosure are formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, pharmaceutically acceptable compositions of this disclosure are administered without food. In other embodiments, pharmaceutically acceptable compositions of this disclosure are administered with food.

[0173] The amount of compounds of the present disclosure that may be combined with the carrier materials to produce a composition in a single dosage form will vary depending upon the host treated, the particular mode of administration. Preferably, provided compositions should be formulated so that a dosage of between 0.01 - 100 mg / kg body weight / day of the compound can be administered to a patient receiving these compositions.

[0174] It should also be understood that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated. The amount of a compound of the present disclosure in the composition will also depend upon the particular compound in the composition.Uses of Compounds and Pharmaceutically Acceptable Compositions

[0175] Compounds and compositions described herein are generally useful for the modulation of the activity CDK2. In some embodiments, the compounds and compositions described herein are CDK2 inhibitors.

[0176] Tn some embodiments, the compounds and compositions of the present disclosure are useful for treating diseases and disorders associated with CDK2 activity, including, but not limited to cancers, myeloproliferative disorders, autoimmune disorders, inflammatory disorders, viral infections, fibrotic disorders, and neurodegenerative disorders.

[0177] In some embodiments, the disclosure provides a method of inhibiting the activity of a CDK2, the method comprising contacting a compound of the present disclosure, or a pharmaceutically acceptable salt thereof with the CDK2. In some embodiments, the contacting takes place in vitro. In some embodiments, the contacting takes place in vivo.

[0178] In some embodiments, the disclosure provides a method of treating, preventing or lessening the severity of a disease or disorder associated with CDK2 activity in a patient, including, but not limited to cancers, myeloproliferative disorders, autoimmune disorders, inflammatory disorders, fibrotic disorders, and neurodegenerative disorders, said method comprising administering to a patient in need thereof, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.

[0179] The disclosure further provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease or disorder associated with CDK2 activity.

[0180] The disclosure further provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for treating a disease or disorder associated with CDK2 activity.

[0181] In some embodiments, the disease or disorder associated with CDK2 activity is a CDK2- mediated disease or disorder. In some embodiments, the disease or disorder associated with CDK2 activity is a disease or disorder caused by CDK2 over-activity.

[0182] In some embodiments, the disease or disorder associated with CDK2 activity is cancer.

[0183] Tn some embodiments, the cancer is selected from breast cancer, ovarian cancer, bladder cancer, uterine cancer, prostate cancer, lung cancer, esophageal cancer, head and neck cancer, colorectal cancer, kidney cancer, liver cancer, pancreatic cancer, stomach cancer, melanoma and thyroid cancer.

[0184] In some embodiments, the cancer is characterized by amplification or overexpression of CCNE1 and / or CCNE2.

[0185] In some embodiments, the cancer is breast cancer. In some embodiments, the breast cancer is a breast cancer selected from ER-positive / HR-positive breast cancer, HER2-negative breast cancer, ER-positive / HR-positive breast cancer, HER2-positive breast cancer, triple negative breast cancer (TNBC), inflammatory breast cancer, endocrine resistant breast cancer, trastuzumab resistant breast cancer, breast cancer with primary or acquired resistance to CDK4 / CDK6 inhibition, advanced breast cancer and metastatic breast cancer. In some embodiments the breast cancer is characterized by amplification or overexpression of CCNE1 and / or CCNE2.

[0186] In some embodiments, the cancer is ovarian cancer. In some embodiments, the ovarian cancer is high-grade serous ovarian cancer (HGSOC). In some embodiments the ovarian cancer is characterized by amplification or overexpression of CCNE1 and / or CCNE2.

[0187] In some embodiments, the cancer is bladder cancer. In some embodiments, the bladder cancer is characterized by amplification or overexpression of CCNE1 and / or CCNE2.

[0188] In some embodiments, the cancer is uterine cancer. In some embodiments, the uterine cancer is characterized by amplification or overexpression of CCNE1 and / or CCNE2.

[0189] In some embodiments, the cancer is prostate cancer. In some embodiments, the prostate cancer is characterized by amplification or overexpression of CCNE1 and / or CCNE2.

[0190] In some embodiments, the cancer is lung cancer. In some embodiments, the lung cancer is a lung cancer selected from non-small cell lung cancer, small cell lung cancer, squamous cell carcinoma, adenocarcinoma, and mesothelioma. In some embodiments, the lung cancer is characterized by amplification or overexpression of CCNE1 and / or CCNE2. Tn some embodiments, the lung cancer is CCNE1 amplified squamous cell carcinoma or CCNE1 amplified adenocarcinoma.

[0191] In some embodiments, the cancer is head and neck cancer. In some embodiments, the head and neck cancer is characterized by amplification or overexpression of CCNE1 and / or CCNE2.

[0192] In some embodiments, the cancer is colorectal cancer. In some embodiments, the colorectal cancer is characterized by amplification or overexpression of CCNE1 and / or CCNE2.

[0193] In some embodiments, the cancer is kidney cancer. In some embodiments, the kidney cancer is renal cell carcinoma (RCC). In some embodiments, the kidney cancer is characterized by amplification or overexpression of CCNE1 and / or CCNE2.

[0194] In some embodiments, the cancer is liver cancer. In some embodiments, the liver cancer is hepatocellular carcinoma (HCC). In some embodiments, the liver cancer is characterized by amplification or overexpression of CCNE1 and / or CCNE2.

[0195] In some embodiments, the cancer is pancreatic cancer. In some embodiments, the pancreatic cancer is characterized by amplification or overexpression of CCNE1 and / or CCNE2.

[0196] In some embodiments, the cancer is stomach cancer. In some embodiments, the stomach cancer is characterized by amplification or overexpression of CCNE1 and / or CCNE2.

[0197] In some embodiments, the cancer is melanoma. In some embodiments, the melanoma is characterized by amplification or overexpression of CCNE1 and / or CCNE2. CDK2 expression is regulated by essential melanocytic transcription factor MITF. It has been found that CDK2 depletion suppresses the growth of melanoma (Du et al., Cancer Cell.2004 Dec; 6(6): 565-576)

[0198] In some embodiments, the cancer is thyroid cancer. In some embodiments, the thyroid cancer is characterized by amplification or overexpression of CCNE1 and / or CCNE2.

[0199] In some embodiments, the disease or disorder associated with CDK2 activity is a myeloproliferative disorder.

[0200] In some embodiments, the disease or disorder associated with CDK2 activity is a neurodegenerative disease or disorder. In some embodiments, the neurodegenerative disease or disorder is Alzheimer’s disease (AD). It has been reported that neuronal cell death in subjects suffering from AD is preceded by cell cycle events. Inhibition of one or more CDKs can inhibit cell cycle events and therefore stave off neuronal cell death (Yang et al., J Neurosci. 2003 Apr 1;23(7):2557-2563).

[0201] In some embodiments, the disease or disorder associated with CDK2 activity is a liver disease.

[0202] In some embodiments, the disease or disorder associated with CDK2 activity is liver fibrosis. It has been reported that CCNE1 knockout mice do not develop liver fibrosis upon exposure to pro-fibrotic toxin CCl4, suggesting that liver fibrosis can be treated via administration of a CDK2 inhibitor (Nevzorova, et al., Hepatology.2012 Sep; 56(3): 1140–1149.)

[0203] In some embodiments, the disease or disorder associated with CDK2 activity is Cushing disease. Pituitary cyclin E / E2F1 signaling is a molecular mechanism underlying neuroendocrine regulation of the hypothalamic-pituitary-adrenal axis, and therefore provides a subcellular therapeutic target for CDK2 inhibitors of pituitary ACTH-dependent hypercortisolism, also known as Cushing disease (Liu, et al., J Clin Endocrinol Metab.2015 Jul; 100(7): 2557–2564.).

[0204] In some embodiments, the disease or disorder associated with CDK2 activity is a kidney disease.

[0205] In some embodiments, the disease or disorder associated with CDK2 activity is polycystic kidney disease. It has been reported that CDK2 / CDK5 inhibitor roscovitine yields effective arrest of cystic kidney disease in mouse models of polycystic kidney disease (Bukanov, et al., Nature. 2006 Dec 14;444(7121):949-52).

[0206] In some embodiments, the disease or disorder associated with CDK2 activity is an autoimmune disorder. CDK2 ablation has been shown to promote immune tolerance by supporting the function of regulatory T cells (Chunder et al., J Immunol.2012 Dec 15;189(12):5659-66).

[0207] In some embodiments, the disease or disorder associated with CDK2 activity is an inflammatory disorder. Cyclin E ablation has been shown to attenuate hepatitis in mice, while p27 knockout mice display exacerbation of renal inflammation (Ehedego et al., Oncogene. 2018 Jun;37(25):3329-3339.; Ophascharoensuk et al., Nat Med. 1998 May;4(5):575-80.). In some embodiments, the inflammatory disorder is hepatitis.

[0208] In some embodiments, the compounds and compositions of the present disclosure are useful as male contraceptives. Based on the finding that male CDK2 knockout mice are sterile, CDK2 inhibitors have been studied as possible male contraceptives (Faber, et al., Biol Reprod. 2020 Aug; 103(2): 357–367.). In some embodiments, the present disclosure provides a method ofreducing male fertility comprising administering to a patient in need thereof, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.

[0209] In some embodiments, the compounds and compositions of the present disclosure are useful for treating diseases and disorders associated with CDK5 activity, including, but not limited to cancers, myeloproliferative disorders, autoimmune disorders, inflammatory disorders, viral infections, fibrotic disorders, and neurodegenerative disorders. In some embodiments, the compounds and compositions of the present disclosure are useful for treating neurodegenerative disorders associated with CDK5 activity.Combination Therapies

[0210] Depending upon the particular condition, or disease, to be treated, additional therapeutic agents, which are normally administered to treat that condition, may be administered in combination with compounds and compositions of this disclosure. As used herein, additional therapeutic agents that are normally administered to treat a particular disease, or condition, are known as “appropriate for the disease, or condition, being treated.”

[0211] In certain embodiments, a provided combination, or composition thereof, is administered in combination with another therapeutic agent.

[0212] In some embodiments, the present disclosure provides a method of treating a disclosed disease or condition comprising administering to a patient in need thereof an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof and co-administering simultaneously or sequentially an effective amount of one or more additional therapeutic agents, such as those described herein. In some embodiments, the method includes co-administering one additional therapeutic agent. In some embodiments, the method includes co-administering two additional therapeutic agents. In some embodiments, the combination of the disclosed compound and the additional therapeutic agent or agents acts synergistically.

[0213] Examples of agents that the compounds of the present disclosure may also be combined with include, without limitation: endocrine therapeutic agents, chemotherapeutic agents and other CDK inhibitory compounds.

[0214] In some embodiments, the present disclosure provides a method of treating a disclosed disease or condition comprising administering to a patient in need thereof an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof and co-administering simultaneously or sequentially an effective amount of an endocrine therapeutic agent.

[0215] In some embodiments, the present disclosure provides a method of treating a disclosed disease or condition comprising administering to a patient in need thereof an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof and co-administering simultaneously or sequentially an effective amount of one or more additional CDK inhibitory compounds. In some embodiments, the one or more additional CDK inhibitory compounds are CDK4, or CDK4 / CDK6 inhibitors. In some embodiments, the one or more additional CDK inhibitory compounds are CDK4, CDK6, CDK7 or CDK4 / CDK6 inhibitors. In some embodiments, the one or more additional CDK inhibitory compounds are CDK4 inhibitors. In some embodiments, the one or more additional CDK inhibitory compounds are CDK6 inhibitors. In some embodiments, the one or more additional CDK inhibitory compounds are CDK7 inhibitors. In some embodiments, the one or more additional CDK inhibitory compounds are CDK4 / CDK6 inhibitors.

[0216] In some embodiments, the present disclosure provides a method of treating a disclosed disease or condition comprising administering to a patient in need thereof an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof and co-administering simultaneously or sequentially an effective amount of a chemotherapeutic agent. In some embodiments, the chemotherapeutic agent is a taxane. In some embodiments, the chemotherapeutic agent is a platinum agent. In some embodiments, the chemotherapeutic agent is trastuzumab.

[0217] As used herein, the term “combination,” “combined,” and related terms refers to the simultaneous or sequential administration of therapeutic agents in accordance with this disclosure. For example, a combination of the present disclosure may be administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form.

[0218] The amount of additional therapeutic agent present in the compositions of this disclosure will be no more than the amount that would normally be administered in a composition comprisingthat therapeutic agent as the only active agent. Preferably the amount of additional therapeutic agent in the presently disclosed compositions will range from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent.

[0219] One or more other therapeutic agent may be administered separately from a compound or composition of the present disclosure, as part of a multiple dosage regimen. Alternatively, one or more other therapeutic agents may be part of a single dosage form, mixed together with a compound of this disclosure in a single composition. If administered as a multiple dosage regime, one or more other therapeutic agent and a compound or composition of the present disclosure may be administered simultaneously, sequentially or within a period of time from one another, for example within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 18, 20, 21 , 22, 23, or 24 hours from one another. In some embodiments, one or more other therapeutic agent and a compound or composition the present disclosure are administered as a multiple dosage regimen within greater than 24 hours apart.

[0220] In one embodiment, the present disclosure provides a composition comprising a provided compound or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents. The therapeutic agent may be administered together with a provided compound or a pharmaceutically acceptable salt thereof, or may be administered prior to or following administration of a provided compound or a pharmaceutically acceptable salt thereof. Suitable therapeutic agents are described in further detail below. Tn certain embodiments, a provided compound or a pharmaceutically acceptable salt thereof may be administered up to 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5, hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hours before the therapeutic agent. In other embodiments, a provided compound or a pharmaceutically acceptable salt thereof may be administered up to 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5, hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hours following the therapeutic agent.EXAMPLES

[0221] As depicted in the Examples below, in certain exemplary embodiments, compounds are prepared according to the general procedures provided herein. It will be appreciated that, althoughthe general methods depict the synthesis of certain compounds of the present disclosure, the general methods, and other methods known to one of ordinary skill in the art, can be applied to all compounds and subclasses and species of each of these compounds, as described herein. Example 1: Synthesis Procedures

[0222] Synthesis of 5-(1-(O-((2-oxabicyclo[2.2.2]octan-4-yl)methyl)-n-((s)-2-((s)-2,2- dimethylcyclopropane-1-carbonyl)-6-(5-hydroxypyrazine-2-carbonyl)-2,6-diazaspiro [3.4] octane-8-carbonyl)-L-threonyl) piperidin-4-yl)-2-(trifluoromethyl)benzoic acid (I-90)

[0223] Synthesis of tert-Butyl 4-(3-(methoxycarbonyl)-4-(trifluoromethyl)phenyl)-3,6- dihydropyridine-1(2H)-carboxylate: To a stirred solution of methyl 5-bromo-2- (trifluoromethyl)benzoate (0.750 g, 2.65 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (0.819 g, 2.65 mmol) in a DMF (10 mL) was added K2CO3(1.09 g, 7.95 mmol) at room temperature. The reaction mixture was degassed (purging with nitrogen) for 20 min followed by the addition of Pd(PPh3)4(0.153 g, 0.132 mmol) at the same temperature and heated the reaction mixture at 900C for 3h. Reaction mixture was cooled to room temperature, diluted with water (250 mL) and was extracted with diethyl ether (200 mL × 3). The combined organic extracts were dried over anhydrous Na2SO4and concentrated under reduce pressure. Obtained crude was combined with an identically prepared one more batch and the combined crude product was purified by silica gel column chromatography, using ethyl acetate-hexane = 0:10 →1:9 as gradient, to afforded tert-butyl 4-(3-(methoxycarbonyl)-4- (trifluoromethyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate (1.5 g, 73%) as a colourless liquid. MS: [MH]+286.3.

[0224] Synthesis of tert-Butyl 4-(3-(methoxycarbonyl)-4-(trifluoromethyl)phenyl)piperidine- 1-carboxylate: 10% Pd on activated carbon (0.500 g) was added carefully to a stirred solution of tert-butyl 4-(3-(methoxycarbonyl)-4-(trifluoromethyl)phenyl)-3,6-dihydropyridine-1(2H)- carboxylate (1.00 g, 2.59 mmol) in methanol (12.0 mL) at room temperature under nitrogen and the resulting mixture was hydrogenated under balloon pressure at the same temperature for 2h. [Another batch (0.500 g) was performed in parallel and mixed together prior to work-up and purification]. Combined mixtures were filtered through a celite bed, washed the bed with methanol (50 mL) and collected filtrates were concentrated under reduced pressure to afforded tert-butyl 4- (3-(methoxycarbonyl)-4-(trifluoromethyl)phenyl)piperidine-1-carboxylate(1.35 g, 89%; crude) as a colourless oil. MS: [(M-56)+1]+332.2.

[0225] Synthesis of Methyl 5-(piperidin-4-yl)-2-(trifluoromethyl)benzoate: To a stirred solution of tert-butyl 4-(3-(methoxycarbonyl)-4-(trifluoromethyl)phenyl)piperidine-1-carboxylate (0.900 g, 2.32 mmol) in DCM (10 mL) was added 4M HCl in dioxane (10 mL) at 00C and the resulting reaction mixture was stirred at room temperature for 1h. [Another batch (0.500 g) was performed in parallel and mixed together prior to work-up and purification]. Combined mixtures were concentrated under reduced pressure and the obtained crude product was purified by trituration with n-pentane, to afforded methyl 5-(piperidin-4-yl)-2-(trifluoromethyl)benzoate hydrochloride (1.20 g, quantitative; crude) as a white solid. MS: [MH]+288.3.

[0226] Synthesis of Methyl 5-(1-(o-((2-oxabicyclo[2.2.2]octan-4-yl)methyl)-N-(((4- nitrobenzyl)oxy)carbonyl)-L-threonyl)piperidin-4-yl)-2-(trifluoromethyl)benzoate: To a stirred solution of o-((2-oxabicyclo[2.2.2]octan-4-yl)methyl)-N-(((4-nitrobenzyl)oxy)carbonyl)- L-threonine (0.400 g, 0.94 mmol) in DCM (7 mL) were added DIPEA (0.360 g, 2.84 mmol) and HATU (0.720 g, 1.895 mmol) at 00C under nitrogen. After 10 min of stirring at the same temperature, was added methyl 5-(piperidin-4-yl)-2-(trifluoromethyl)benzoate (0.408 g, 1.42 mmol) and stirring was continued for 1h at room temperature. Reaction mixture slowly poured into ice water (50.0 mL) and was extracted with ethyl acetate (50 mL × 3). Combined organic extracts were washed with brine (20.0 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to get a crude product. The crude product was purified by column chromatography on silica gel, using MeOH: DCM = 1:19 to afforded methyl 5-(1-(o-((2- oxabicyclo[2.2.2]octan-4-yl)methyl)-N-(((4-nitrobenzyl)oxy)carbonyl)-L-threonyl) piperidin-4- yl)-2-(trifluoromethyl)benzoate (0.800 g, quantitative) as an oil. MS: [MH]+692.4.

[0227] Synthesis of Methyl 5-(1-(o-((2-oxabicyclo[2.2.2]octan-4-yl)methyl)-L- threonyl)piperidin-4-yl)-2-(trifluoromethyl)benzoate: 10% Pd in activated carbon (0.400 g) was added carefully to a stirred solution of methyl 5-(1-(o-((2-oxabicyclo[2.2.2]octan-4- yl)methyl)-N-(((4-nitrobenzyl)oxy)carbonyl)-L-threonyl)piperidin-4-yl) -2- (trifluoromethyl)benzoate (0.800 g, 1.15 mmol) in methanol (10 mL) at room temperature under nitrogen and the resulting mixture was hydrogenated under balloon pressure at the same temperature for 2h. Reaction mixture was filtered through a celite bed, washed the bed with methanol (50 mL) and collected filtrates were concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, using MeOH:DCM = 1:19 to afforded methyl 5-(1-(o-((2-oxabicyclo[2.2.2]octan-4-yl)methyl)-L-threonyl)piperidin-4-yl)-2- (trifluoromethyl)benzoate (0.320 g, 54%) as a white solid. MS: [MH]+513.4.

[0228] Synthesis of intermediate ((s)-2-((s)-2,2-dimethylcyclopropane-1-carbonyl)-6-(5- hydroxypyrazine-2-carbonyl)-2,6- diazaspiro [3.4] octane-8-carboxylic acid is mentioned under 2- (1-(O-((2-oxabicyclo[2.2.2]octan-4-yl)methyl)-N-((S)-2-((S)-2,2-dimethylcyclopropane-1- carbonyl)-6-(5-hydroxypyrazine-2-carbonyl)-2,6-diazaspiro[3.4]octane-8-carbonyl)-L- threonyl)piperidin-4-yl)-5-(trifluoromethyl)benzoic acid (I-10)

[0229] Synthesis of Methyl 5-(1-(o-((2-oxabicyclo[2.2.2]octan-4-yl)methyl)-n-((s)-2-((s)-2,2- dimethylcyclopropane-1- carbonyl)-6- (5-hydroxypyrazine-2-carbonyl) -2,6-diazaspiro [3.4] octane-8-carbonyl)-L-threonyl)piperidin-4-yl)-2-(trifluoromethyl)benzoate: To a stirred solution of methyl 5-(1-(o-((2-oxabicyclo [2.2.2] octan-4-yl)methyl)-L-threonyl)piperidin-4-yl)- 2-(trifluoromethyl) benzoate (0.307 g, 0.60 mmol) in DCM (3 mL) were added ((s)-2-((s)-2,2- dimethylcyclopropane-1-carbonyl)-6-(5-hydroxypyrazine-2-carbonyl)-2,6-diazaspiro[3.4] octane-8-carboxylic acid (0.150 g, 0.40 mmol) and DCC (0.165 g, 0.802 mmol) sequentially at 0 °C under nitrogen and the resulting reaction mixture was stirred for 3h at room temperature. Reaction mixture was slowly poured into ice water (50.0 mL) and was extracted with DCM (50.0 mL × 3). Combined organic extracts were washed with brine (20.0 mL), dried over anhydrous Na2SO4and concentrated under reduced pressure to get a crude product. The crude product was purified by column chromatography on silica gel, using MeOH: DCM = 0:1 →1:19 to afforded methyl 5-(1-(o-((2-oxabicyclo[2.2.2]octan-4-yl)methyl)-n-((s)-2-((s)-2,2-dimethylcyclopropane- 1- carbonyl)-6- (5-hydroxypyrazine-2-carbonyl) -2,6-diazaspiro [3.4] octane-8-carbonyl)-L- threonyl)piperidin-4-yl)-2-(trifluoromethyl)benzoate (0.200 g, 57%) as a white solid. MS: [MH]+869.7.

[0230] Synthesis of 5-(1-(O-((2-oxabicyclo[2.2.2]octan-4-yl)methyl)-n-((s)-2-((s)-2,2- dimethylcyclopropane-1-carbonyl)-6-(5-hydroxypyrazine-2-carbonyl)-2,6-diazaspiro [3.4] octane-8-carbonyl)-L-threonyl) piperidin-4-yl)-2-(trifluoromethyl)benzoic acid I-90: To a stirred solution of methyl 5-(1-(o-((2-oxabicyclo[2.2.2]octan-4-yl)methyl)-n-((s)-2-((s)-2,2- dimethylcyclopropane-1-carbonyl)-6-(5-hydroxypyrazine-2-carbonyl)-2,6-diazaspiro [3.4] octane-8-carbonyl)-L-threonyl)piperidin-4-yl)-2-(trifluoromethyl)benzoate (0.170 g, 0.19 mmol) in a mixture of THF-water-MeOH (6:1.5:1.5; 4.5 mL) was added lithium hydroxide monohydrate (0.024 g, 0.58 mmol) at room temperature and stirred for 3h at the same temperature. Reaction was concentrated under reduced pressure, obtained crude was diluted with water (25 mL), acidified (pH ~ 2-3) with an aqueous solution of 1N HCl and was extracted with ethyl acetate (50 mL × 3). Combined organic extracts were washed with brine (20.0 mL), dried over anhydrous Na2SO4and concentrated under reduced pressure. The crude product was purified by prep-HPLC, 0.1% formic acid in water-acetonitrile as gradient, to afford 5-(1-(o-((2-oxabicyclo [2.2.2] octan-4-yl)methyl)- n-((s)-2-((s)-2,2-dimethylcyclopropane-1-carbonyl)-6-(5-hydroxypyrazine-2-carbonyl)-2,6- diazaspiro [3.4] octane-8-carbonyl)-L-threonyl)piperidin-4-yl)-2-(trifluoromethyl)benzoic acid I-90 (0.040 g, 24%) as an off white solid.1H-NMR (400 MHz, DMSO-d6) δ 13.75-12.55 (br, 2H), 8.35-8.25 (m 1H), 7.94-7.89 (m, 1H), 7.77-7.68 (m, 1H), 7.61 (s, 1H), 7.53 (brs, 1H), 6.55-6.60 (br, 1H), 4.92 (br. s, 1H), 4.60-4.52 (m, 1H), 4.19-3.95 (m, 4H), 3.90-3.72 (m, 3H), 3.69-3.64 (m, 2H), 3.56 (s, 2H), 3.50-3.30 (m, 4H; merged in moisture from DMSO-d6), 3.20-3.10 (m, 2H), 3.01- 2.99 (m, 2H), 2.50 (2H, merged in DMSO-d6), 1.92-1.80 (m, 4H), 1.56-1.51 (t, J=8.8 Hz, 4H), 1.42-1.35 (m, 3H), 1.30-1.29 (m, 1H), 1.12-1.03 (m, 8H), 0.85-0.84 (m, 1H), 0.67-0.66 (m, 1H). MS: [MH]+855.7.

[0231] Synthesis of intermediate Methyl 2-(1-(O-((2-oxabicyclo[2.2.2]octan-4-yl)methyl)-L- threonyl)piperidin-4-yl)-5-(trifluoromethyl)benzoate

[0232] Synthesis of ethyl 2-(piperidin-4-yl)-5-(trifluoromethyl)benzoate

[0233] Synthesis of tert-Butyl 4-(2-(ethoxycarbonyl)-4-(trifluoromethyl)phenyl)-3,6- dihydropyridine-1(2H)-carboxylate: To a stirred solution of ethyl 2-bromo-5- (trifluoromethyl)benzoate (1.0 g, 3.37 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.04 g, 3.37 mmol) in DMF (10 mL) was added K2CO3(1.39 g, 10.13 mmol) at room temperature. Reaction mixture was degassed (purging with nitrogen) for 20 min, followed by the addition of Pd(PPh3)4(0.19 g, 0.168 mmol) at the same temperature and the resulting mixture was heated at 900C for 3h. [Two more identical batches were performed and worked up all together]. After cooling to room temperature, combined reaction mixtures were diluted with water (250 mL) and extracted with ethyl acetate (500 mL × 3). Combined organic extracts were dried over anhydrous Na2SO4and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography, using ethyl acetate- hexane = 0:1→0.7:9.3 as gradient, to afforded tert-butyl 4-(2-(ethoxycarbonyl)-4-(trifluoromethyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate (3.0 g, 52%) as a colourless oil. MS: [(M-100)+H]+300.3.

[0234] Synthesis of tert-Butyl 4-(2-(ethoxycarbonyl)-4-(trifluoromethyl)phenyl)piperidine-1- carboxylate: To a stirred solution of tert-butyl 4-(2-(ethoxycarbonyl)-4-(trifluoromethyl)phenyl)- 3,6-dihydropyridine-1(2H)-carboxylate (2.0 g, 5.01 mmol) in a methanol (20 mL) was added 10% Pd in activated carbon (2.0 g) carefully at room temperature under nitrogen and the resulting mixture was hydrogenated under balloon pressure at the same temperature for 3h. Reaction mixture was filter through a celite bed, washed the bed with methanol (150 mL) and collected filtrates were concentrated under reduced pressure to afforded tert-butyl 4-(2-(ethoxycarbonyl)-4- (trifluoromethyl)phenyl)piperidine-1-carboxylate (1.8 g, 89%; crude) as a colourless oil. MS: [(M- 100)+H]+302.4.

[0235] Synthesis of Ethyl 2-(piperidin-4-yl)-5-(trifluoromethyl)benzoate: To a stirred solution of tert-butyl 4-(2-(ethoxycarbonyl)-4-(trifluoromethyl)phenyl)piperidine-1-carboxylate (1.8 g, 4.48 mmol) in DCM (10 mL) was added 4M HCl in dioxane (15 mL) at 00C and stirred at room temperature for 1h. Reaction mixture was concentrated under reduced pressure to obtained crude product, which was purified by trituration using n-pentane, to afforded ethyl 2-(piperidin-4-yl)-5- (trifluoromethyl)benzoate hydrochloride (1.5 g, quantitative; crude) as a white solid.1H-NMR (400 MHz, DMSO-d6) δ 9.01 (s, 2H), 8.00-7.97 (d, J=11.2 Hz, 2H), 7.65-7.63 (d, J=8.4 Hz, 1H), 4.38-4.33 (m, 2H), 3.57-3.51 (t, J=11.2 Hz, 1H), 3.00 (br. s, 2H), 2.01-1.88 (m, 4H), 1.36-1.33 (t, J=7.2 Hz, 3H). MS: [MH]+302.1.

[0236] Synthesis of methyl 2-(1-(O-((2-oxabicyclo[2.2.2]octan-4-yl)methyl)-L- threonyl)piperidin-4-yl)-5-(trifluoromethyl)benzoate

[0237] Synthesis of Methyl L-threoninate: To a stirred solution of methyl (tert-butoxycarbonyl)- L-threoninate (20.0 g, 85.78 mmol) in DCM (100 mL) was added 4M HCl in dioxane (40 mL) at 00C and stirred at room temperature for 2h. [Another identical batch was performed and worked up together]. Combined reaction mixtures were concentrated under reduced pressure. The obtained crude product was purified by trituration using n-pentane, to afforded methyl L-threoninate (45.0 g, quantitative; crude). MS: [MH]+134.2.

[0238] Synthesis of Methyl trityl-L-threoninate: To a stirred solution methyl L-threoninate (14.5 g, 109.02 mmol) in DCM (100 mL) were added TEA (55.13 g, 544.82 mmol) and (chloromethanetriyl)tribenzene (36.36 g, 130.75 mmol) sequentially at 00C under nitrogen and stirred for 30 min at the same temperature. [Two identical batches with 5.0 g and 12.5 g were performed and combined prior to work-up]. Combined reaction mixtures were slowly poured into water (300 mL) and was extracted with DCM (300 mL × 3). Combined organic extracts were wash with brine (200 mL), dried over anhydrous Na2SO4and concentrated in vacuuo. The crude product was purified by silica gel column chromatography, using ethyl acetate-hexane = 0:1→2:3 as gradient, to afforded methyl trityl-L-threoninate (48.0 g, 53%) as a yellow sticky compound.1H- NMR (400 MHz, DMSO-d6) δ 7.43-7.42 (d, J=7.6 Hz, 6H), 7.29-7.26 (t, J=7.2 Hz, 6H), 7.21-7.17 (t, J=7.2 Hz, 3H), 5.04-5.03(d, J=4.4 Hz, 1H), 3.96-3.91 (m, 1H), 3.22-3.16 (m, 1H), 3.02 (s, 3H), 2.69-2.67(d, J=10.0 Hz, 1H), 1.99 (s, 3H), 1.09-1.07 (d, J=6.4 Hz, 3H).

[0239] Synthesis of Methyl (2S, 3S)-3-methyl-1-tritylaziridine-2-carboxylate: To a stirred solution methyl trityl-L-threoninate (35.0 g, 93.28 mmol) in THF (300 mL) was added TEA (26.7 mL, 186.57 mmol) at 00C and stirred the reaction mixture for 20 minutes. Mesyl chloride (8.9 mL, 111.94 mmol) was, then, added drop wise into the reaction mixture at the same temperature over the period of 10 minutes and the resulting mixture was stirred at 800C for 24h. Reaction mixture was cool to room temperature and diluted with water (50 mL) and was extracted with ethyl acetate (50 mL × 3). Combined organic extracts were washed with brine (50 mL), dried over anhydrous Na2SO4and concentrated in vacuuo. The crude product was purified by silica gel column chromatography, using ethyl acetate-hexane = 0:1→0.8 as gradient, to afforded methyl (2S, 3S)-3-methyl-1-tritylaziridine-2-carboxylate (22.0 g, 66%) as a white solid.1H-NMR (400 MHz, DMSO-d6) δ 7.44-7.42 (d, J=7.6 Hz, 6H), 7.34-7.30 (t, J=7.2 Hz, 6H), 7.28-7.19 (m, 3H), 3.67 (s, 3H), 1.73-1.71 (d, J=6.4 Hz, 1H), 1.59-1.53 (m, 1H), 1.29-1.28 (d, J=5.2 Hz, 3H).

[0240] Synthesis of 2-Methyl 1-(4-nitrobenzyl) (2S,3S)-3-methylaziridine-1,2-dicarboxylate: To a stirred suspension of methyl (2S, 3S)-3-methyl-1-tritylaziridine-2-carboxylate (2.0 g, 5.60 mmol) in DCM-MeOH mixture (1:3; 20 mL) was added TFA (10.0 mL) at 0 °C and the resulting reaction mixture was stirred at room temperature for 2h. Reaction mixture was concentrated under reduced pressure till all methanol was distilled-off. Obtained crude was dilute with water (30 mL) and was extracted with diethyl ether (30 mL × 3). Collected aqueous layers was basified (pH~9) with the addition of solid NaHCO3and diluted with ethyl acetate (30 mL). To the stirred biphasic solution, was added 4-nitrobenzylchloroformate (1.80 g, 8.403 mmol) slowly at 00C and stirred the reaction mixture at room temperature for 16h. Reaction mixture diluted with water (30 mL) and was extracted with ethyl acetate (50 mL × 2). Combined organic extracts were washed with brine (30 mL), dried over anhydrous Na2SO4and concentrated in vacuuo. The crude product was purified by silica gel column chromatography, using ethyl acetate-hexane = 0:1→3:7 as gradient, to afforded 2-methyl 1-(4-nitrobenzyl) (2S,3S)-3-methylaziridine-1,2-dicarboxylate (1.0 g, 62%) as a white solid.1H-NMR (400 MHz, DMSO-d6) δ 8.25-8.23 (d, J=8.0 Hz, 2H), 7.65-7.63 (d, J=8.0 Hz, 2H), 5.24 (s, 2H), 3.73-3.69 (d, J=14.8 Hz, 3H), 3.43-3.41 (d, J=6.8 Hz, 1H), 3.05-3.01 (m, 1H), 1.21-1.19 (d, J=5.6 Hz, 3H).

[0241] Synthesis of Methyl O-((2-oxabicyclo[2.2.2]octan-4-yl)methyl)-N-(((4- nitrobenzyl)oxy)carbonyl)-L-threoninate: To a stirred solution of 2-methyl 1-(4-nitrobenzyl)(2S,3S)-3-methylaziridine-1,2-dicarboxylate (1.0 g, 3.40 mmol) and (2-oxabicyclo[2.2.2]octan-4- yl)methanol (0.480 g, 3.40 mmol) in CHCl3(12 mL) was added BF3.Et2O (0.240 g, 1.70 mmol) drop wise at 00C and the resulting reaction mixture was stirred at room temperature for 2h. Reaction mixture was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography, using ethyl acetate-hexane = 0:1→4:6 as gradient, to afforded methyl O-((2-oxabicyclo[2.2.2]octan-4-yl)methyl)-N-(((4-nitrobenzyl)oxy)carbonyl)- L-threoninate (0.550 g, 39%) as a colourless gummy mass. MS: [MH]+437.4.

[0242] Synthesis of O-((2-oxabicyclo[2.2.2]octan-4-yl)methyl)-N-(((4- nitrobenzyl)oxy)carbonyl)-L-threonine: To a stirred solution of methyl O-((2- oxabicyclo[2.2.2]octan-4-yl)methyl)-N-(((4-nitrobenzyl)oxy)carbonyl)-L-threoninate (1.3 g, 2.98 mmol) in a mixture of THF-water (4:1; 10 mL) was added lithium hydroxide monohydrate (0.375 g, 8.94 mmol) at room temperature and the resulting reaction mixture was stirred at room temperature for 3h. Reaction mixture was concentrated under reduced pressure, obtained crude was diluted with water (5 mL) and was extracted with diethyl ether to get rid of unwanted organic impurities. Separated aqueous layer was acidified (pH ~ 4) with an aqueous solution of 1N HCl and was extracted with ethyl acetate (50 mL × 2). Combined organic extracts were washed with brine (30 mL), dried over anhydrous Na2SO4and concentrated in vacuo to afforded O-((2- oxabicyclo[2.2.2]octan-4-yl)methyl)-N-(((4-nitrobenzyl)oxy)carbonyl)-L-threonine (1.0 g, 82%) as a colourless liquid. MS: [MH]+ 423.4.

[0243] Synthesis of Ethyl 2-(1-(O-((2-oxabicyclo[2.2.2]octan-4-yl)methyl)-N-(((4- nitrobenzyl)oxy)carbonyl)-L-threonyl)piperidin-4-yl)-5-(trifluoromethyl)benzoate: To a stirred solution of O-((2-oxabicyclo[2.2.2]octan-4-yl)methyl)-N-(((4-nitrobenzyl)oxy)carbonyl)- L-threonine (0.400 g, 0.94 mmol) in DCM (5.0 mL) were added DIPEA (0.366 g, 2.84 mmol) and HATU (0.722 g, 1.89 mmol) at 00C under nitrogen. After 10 minutes of stirring at the same temperature, was added ethyl 2-(piperidin-4-yl)-5-(trifluoromethyl)benzoate (0.427 g, 1.42 mmol) and stirring was continued for another 1h at room temperature. Reaction mixture was slowly poured into ice water (50 mL) and was extracted with ethyl acetate (100 mL × 3). Combined organic extracts were wash with brine (20 mL), dried over anhydrous Na2SO4and concentrated under reduced pressure to get a crude product. The crude product was purified by column chromatography on silica gel (DCM-MeOH = 19:1) to afford ethyl 2-(1-(o-((2-oxabicyclo [2.2.2]octan-4-yl)methyl)-N-(((4-nitrobenzyl)oxy)carbonyl)-L-threonyl) piperidin-4-yl)-5- (trifluoromethyl)benzoate (0.350 g, 52%) as an oily liquid. MS: [MH]+706.5.

[0244] Synthesis of Methyl 2-(1-(O-((2-oxabicyclo[2.2.2]octan-4-yl)methyl)-L- threonyl)piperidin-4-yl)-5-(trifluoromethyl)benzoate: To a stirred solution of ethyl 2-(1-(o-((2- oxabicyclo[2.2.2]octan-4-yl)methyl)-N-(((4-nitrobenzyl)oxy)carbonyl)-L-threonyl) piperidin-4- yl)-5-(trifluoromethyl)benzoate (0.350 g, 0.49 mmol) in a methanol (5 mL) was added carefully 10% Pd in activated carbon (0.150 g) at room temperature under nitrogen and the resulting mixture was hydrogenated under balloon pressure at the same temperature for 2h. Reaction mixture was filtered through a celite bed, washed the bed with methanol (50 mL) and collected filtrates were concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (DCM:MeOH = 19:1) to afford ethyl 2-(1-(o-((2-oxabicyclo[2.2.2]octan-4- yl)methyl)-L-threonyl)piperidin-4-yl)-5-(trifluoromethyl) benzoate (0.190 g, 72%) as a colourless sticky oil. MS: [MH]+527.5.

[0245] Synthesis of 2-(1-(O-((2-oxabicyclo[2.2.2]octan-4-yl)methyl)-N-((S)-2-((S)-2,2- dimethylcyclopropane-1-carbonyl)-6-(5-hydroxypyrazine-2-carbonyl)-2,6- diazaspiro[3.4]octane-8-carbonyl)-L-threonyl)piperidin-4-yl)-5-(trifluoromethyl)benzoic acid (I-44)

[0246] Synthesis of intermediate (R)-3-((S)-6-benzyl-2,6-diazaspiro[3.4]octane-8-carbonyl)-4- phenyloxazolidin-2-one is mentioned under synthesis for 2-(1-(O-((2-oxabicyclo[2.2.2]octan-4-yl)methyl)-N-((S)-6-(5-hydroxypyrazine-2-carbonyl)-2-(1-(trifluoromethyl)cyclopropane-1- carbonyl)-2,6-diazaspiro[3.4]octane-8-carbonyl)-L-threonyl) piperidin-4-yl)-5- (trifluoromethyl)benzoic acid I-1

[0247] Synthesis of (R)-3-((S)-6-benzyl-2-((S)-2,2-dimethylcyclopropane-1-carbonyl)-2,6- diazaspiro[3.4]octane-8-carbonyl)-4-phenyloxazolidin-2-one: To a stirred solution of (S)-2,2- dimethylcyclopropane-1-carboxylic acid (4.00 g, 35.06 mmol) in DCM (60 mL) were added DIPEA (22.57 g, 174.96 mmol) and HATU (19.95 g, 52.5 mmol) sequentially at 00C under nitrogen. After 10 minutes of stirring at the same temperature, was added (R)-3-((S)-6-benzyl-2,6- diazaspiro[3.4]octane-8-carbonyl)-4-phenyloxazolidin-2-one (19.20 g, 49.08 mmol) and stirred at room temperature for 16 h. Reaction mixture was slowly poured into ice water (150 mL) and was extracted with ethyl acetate (150 mL × 3). Combined organic extracts were dried over anhydrous Na2SO4and concentrated under reduce pressure. Obtained crude product crude was purified by reverse phase (C-18) silica gel column chromatography using acetonitrile-water = 0:1→1:1 as gradient, to afforded (R)-3-((S)-6-benzyl-2-((S)-2,2-dimethylcyclopropane-1-carbonyl)-2,6- diazaspiro[3.4]octane-8-carbonyl)-4-phenyloxazolidin-2-one (8.0 g, 34%) as a brown solid. MS: [MH]+488.3.

[0248] Synthesis of (R)-3-((S)-2-((S)-2,2-dimethylcyclopropane-1-carbonyl)-2,6- diazaspiro[3.4]octane-8-carbonyl)-4-phenyloxazolidin-2-one: To a stirred solution of (R)-3- ((S)-6-benzyl-2-((S)-2,2-dimethylcyclopropane-1-carbonyl)-2,6-diazaspiro[3.4]octane-8- carbonyl)-4-phenyloxazolidin-2-one (4.00 g, 8.21 mmol) in a mixture of ethyl acetate-methanol (1:1, 60 mL) was added 10% palladium on activated carbon (2.0 g) at room temperature under nitrogen and the resulting mixture hydrogenated under balloon pressure at room temperature for 9h. Reaction mixture filtered through celite bed, washed the bed with ethyl acetate (200 mL) and collected filtrates were concentrated under reduced pressure to afford (R)-3-((S)-2-((S)-2,2- dimethylcyclopropane-1-carbonyl)-2,6-diazaspiro[3.4]octane-8-carbonyl)-4-phenyloxazolidin-2- one (3.7 g, quantitative yield; crude) as an off white solid. MS: [MH]+398.5.

[0249] Synthesis of (R)-3-((S)-2-((S)-2,2-dimethylcyclopropane-1-carbonyl)-6-(5- hydroxypyrazine-2-carbonyl)-2,6-diazaspiro[3.4]octane-8-carbonyl)-4-phenyloxazolidin-2- one: To a stirred solution of 5-hydroxypyrazine-2-carboxylic acid (1.8 g, 12.85 mmol) in DCM(60.0 mL) were added DIPEA (4.97 g, 38.56 mmol) and HATU (7.32 g, 19.28 mmol) at 00C under nitrogen. After 10 minutes of stirring at the same temperature, was added (R)-3-((S)-2-((S)-2,2- dimethylcyclopropane-1-carbonyl)-2,6-diazaspiro[3.4]octane-8-carbonyl)-4-phenyloxazolidin-2- one (3.57 g, 8.99 mmol; crude) and stirred at room temperature for 12h. Reaction mixture was slowly poured into ice water (80 mL) and was extracted with ethyl acetate (100 mL × 3). Combined organic extracts were washed with brine (150 mL), dried over anhydrous Na2SO4and concentrated under reduced pressure to get a crude product. The resulting crude was purified by reverse phase (C-18) silica gel column chromatography using acetonitrile-water = 0:1→4:1 as gradient, to afforded (R)-3-((S)-2-((S)-2,2-dimethylcyclopropane-1-carbonyl)-6-(5-hydroxypyrazine-2- carbonyl)-2,6 diazaspiro [3.4] octane-8-carbonyl)-4-phenyloxa zolidin-2-one (1.3 g, 55 %) as a brown solid. MS: [MH]+520.4

[0250] Synthesis of (S)-2-((S)-2,2-dimethylcyclopropane-1-carbonyl)-6-(5-hydroxypyrazine- 2-carbonyl)-2,6-diazaspiro[3.4]octane-8-carboxylic acid: To a stirred solution of (R)-3-((S)-2- ((S)-2,2-dimethylcyclopropane-1-carbonyl)-6-(5-hydroxypyrazine-2-carbonyl)-2,6- diazaspiro[3.4]octane-8-carbonyl)-4-phenyloxa zolidin-2-one (1.30 g, 2.50 mmol) in THF (9 mL) was added H2O2(13 mL) at 00C and stirred at room temperature for 2h. An aqueous (1 mL) solution of lithium hydroxide monohydrate (0.168 g, 4.00 mmol) was added at 00C and the resulting reaction mixture was stirred at 00C for an additional 10 min. Reaction mixture was diluted with water (10 mL) and was extracted with ethyl acetate (20 mL x 2) to remove unwanted organic impurities. Aqueous solution was acidified (pH ~ 2-3) with an aqueous solution of 1N HCl and was extracted with 20 % IPA-CHCl3solution (100 mL × 3). Combined organic extracts were washed with brine (50 mL), dried over anhydrous Na2SO4and concentrated under reduced pressure to get a crude product. The crude product was purified by reverse phase column chromatography using acetonitrile-water = 0:1→2:8 to afford (S)-2-((S)-2,2- dimethylcyclopropane-1-carbonyl)-6-(5-hydroxypyrazine-2-carbonyl)-2,6-diazaspiro[3.4]octane- 8-carboxylic acid (0.400 g, 42%) as an off white solid. MS: [MH]+375.5

[0251] Synthesis of Ethyl 2-(1-(O-((2-oxabicyclo[2.2.2]octan-4-yl)methyl)-N-((S)-2-((S)-2,2- dimethylcyclopropane-1-carbonyl)-6-(5-hydroxypyrazine-2-carbonyl)-2,6- diazaspiro[3.4]octane-8-carbonyl)-L-threonyl) piperidin-4-yl)-5-(trifluoromethyl)benzoate: To a stirred solution of (S)-2-((S)-2,2-dimethylcyclopropane-1-carbonyl)-6-(5-hydroxypyrazine-2-carbonyl)-2,6-diazaspiro [3.4]octane-8-carboxylic acid (0.150 g, 0.40 mmol) in DCM (3 mL) were added ethyl 2-(1-(O-((2-oxabicyclo[2.2.2]octan-4-yl)methyl)-L-threonyl)piperidin-4-yl)-5- (trifluoromethyl) benzoate (0.210 g, 0.40 mmol) and DCC (0.165 g, 0.80 mmol) sequentially at 00C under nitrogen and the resulting reaction mixture stirred at room temperature for 3h. Reaction mixture slowly poured into ice water (50 mL) and was extracted with DCM (50 mL × 3). Combined organic extracts were wash with brine (20 mL), dried over anhydrous Na2SO4and concentrated under reduced pressure to get a crude product. The crude product was purified by silica gel column chromatography using DCM: MeOH = 20 →1 as gradient, to afforded Ethyl 2-(1-(O-((2- oxabicyclo[2.2.2]octan-4-yl)methyl)-N-((S)-2-((S)-2,2-dimethylcyclopropane-1-carbonyl)-6-(5- hydroxypyrazine-2-carbonyl)-2,6-diazaspiro[3.4]octane-8-carbonyl)-L-threonyl) piperidin-4-yl)- 5-(trifluoromethyl)benzoate (0.180 g, 51%) as a white solid. MS: [MH]+883.7.

[0252] Synthesis of 2-(1-(O-((2-oxabicyclo[2.2.2]octan-4-yl)methyl)-N-((S)-2-((S)-2,2- dimethylcyclopropane-1-carbonyl)-6-(5-hydroxypyrazine-2-carbonyl)-2,6- diazaspiro[3.4]octane-8-carbonyl)-L-threonyl)piperidin-4-yl)-5-(trifluoromethyl)benzoic acid: To a stirred solution of Ethyl 2-(1-(O-((2-oxabicyclo[2.2.2]octan-4-yl)methyl)-N-((S)-2- ((S)-2,2-dimethylcyclopropane-1-carbonyl)-6-(5-hydroxypyrazine-2-carbonyl)-2,6- diazaspiro[3.4]octane-8-carbonyl)-L-threonyl) piperidin-4-yl)-5-(trifluoromethyl)benzoate (0.180 g, 0.203 mmol) in a mixture of THF-water (3:1; 4 mL) was added lithium hydroxide monohydrate (0.0146 g, 0.611 mmol) at room temperature and the resulting reaction mixture was heated at 500 ⁰C for 3h. After cooling to room temperature, the reaction mass was diluted with water (40 mL) and was extracted with diethyl ether (50 mL) to remove unwanted impurities. Aqueous part was acidified (pH ~ 2-3) with an aqueous solution of 1N HCl and was extracted with ethyl acetate (50 mL × 3). Combined organic extracts were wash with brine (20 mL), dried over anhydrous Na2SO4and concentrated under reduced pressure to get a crude product. The crude product was purified by prep-HPLC, 0.1% formic acid in water-acetonitrile as gradient, to afford 2-(1-(o-((2-oxabicyclo [2.2.2]octan-4-yl)methyl)-N-((S)-2-((S)-2,2-dimethylcyclopropane-1-carbonyl)-6-(5- hydroxypyrazine-2-carbonyl)-2,6-diazaspiro[3.4]octane-8-carbonyl)-L-threonyl)piperidin-4-yl)- 5-(trifluoromethyl) benzoic acid (0.030, 17%) as a white solid.1H-NMR (400 MHz, DMSO-d6) δ 13.48-12.58 (br, 2H), 8.49-8.31 (m, 1H), 7.96-7.76 (m, 3H), 7.59 (brs, 1H), 6.58 (brs, 1H), 5.00- 4.82 (m, 1H), 4.62-4.52 (m, 1H), 4.21-3.82 (m, 5H), 3.80-3.50 (m, 6H), 3.50-3.3 (m, 2H; merged in moisture from DMSO-d6), 3.20-3.01 (m, 2H), 2.70-2.50 (m, 2H; merged in DMSO-d6), 1.82(brs, 4H), 1.64-1.48 (m, 4H), 1.45-1.20 (m, 3H), 1.12-1.03 (m, 7H), 0.85 (br. s, 1H), 0.67 (brs, 1H). MS: [MH]+855.7 (7 aliphatic are there to be accountable and being messy in DMSO-d6but it appeared well when added a drop of TFA).

[0253] Synthesis of 5-(1-(O-((2-oxabicyclo[2.2.2]octan-4-yl)methyl)-N-((S)-6-(5- hydroxypyrazine-2-carbonyl)-2-(1-(trifluoromethyl)cyclopropane-1-carbonyl)-2,6- diazaspiro[3.4]octane-8-carbonyl)-D-threonyl)piperidin-4-yl)-2-(trifluoromethyl)benzoic acid I-82

[0254] Synthetic procedure of methyl 5-(1-(O-((2-oxabicyclo[2.2.2]octan-4-yl)methyl)-D- threonyl)piperidin-4-yl)-2-(trifluoromethyl)benzoate mentioned under 5-(1-(O-((2- oxabicyclo[2.2.2]octan-4-yl)methyl)-n-((s)-2-((s)-2,2-dimethylcyclopropane-1-carbonyl)-6-(5- hydroxypyrazine-2-carbonyl)-2,6-diazaspiro [3.4] octane-8-carbonyl)-L-threonyl) piperidin-4- yl)-2-(trifluoromethyl)benzoic acid I-90

[0255] Synthesis of Methyl5-(1-(O-((2-oxabicyclo[2.2.2]octan-4-yl)methyl)-N-((S)-6-(5- hydroxypyrazine-2carbonyl)-2-(1-(trifluoromethyl)cyclopropane-1-carbonyl)-2,6- diazaspiro[3.4]octane-8-carbonyl)-D-threonyl) piperidin-4-yl)-2-(trifluoromethyl)benzoate: To a stirred solution of (S)-6-(5-hydroxypyrazine-2-carbonyl)-2-(1- (trifluoromethyl)cyclopropane-1-carbonyl)-2,6-diazaspiro[3.4]octane-8-carboxylic acid (0.200 g,0.48 mmol) in DCM (3 mL) were added methyl 5-(1-(O-((2-oxabicyclo[2.2.2]octan-4-yl)methyl)- D-threonyl)piperidin-4-yl)-2-(trifluoromethyl)benzoate (0.297 g, 0.57 mmol) and DCC (0.200 g, 0.96 mmol) sequentially at 00C under nitrogen and the resulting reaction mixture stirred for 1h at room temperature. Reaction mixture slowly poured into ice water (40 mL) and extracted with DCM (40 mL × 3). Combined organic extracts were wash with brine (20 mL), dried over anhydrous Na2SO4and concentrated under reduced pressure to get a crude product. The crude product was purified by column chromatography on silica gel DCM:MeOH = 0:1→1:19 to afforded methyl 5-(1-(O-((2-oxabicyclo[2.2.2]octan-4-yl)methyl)-N-((S)-6-(5-hydroxypyrazine- 2-carbonyl)-2-(1-(trifluoromethyl)cyclopropane-1-carbonyl) 2,6diazaspiro [3.4]octane-8- carbonyl)-D-threonyl)piperidin-4-yl)-2-(trifluoromethyl)benzoate (0.160 g, 36%) as an off-white solid. MS: [MH]+909.6.

[0256] Synthesis of 5-(1-(O-((2-oxabicyclo[2.2.2]octan-4-yl)methyl)-N-((S)-6-(5- hydroxypyrazine-2-carbonyl)-2-(1-(trifluoromethyl)cyclopropane-1-carbonyl)-2,6- diazaspiro[3.4]octane-8-carbonyl)-D-threonyl)piperidin-4-yl)-2-(trifluoromethyl)benzoic acid (I-82): To a stirred solution of methyl 5-(1-(O-((2-oxabicyclo[2.2.2]octan-4-yl)methyl)-N- ((S)-6-(5-hydroxypyrazine-2-carbonyl)-2-(1-(trifluoromethyl)cyclopropane-1-carbonyl)- 2,6diazaspiro [3.4] octane-8-carbonyl)-D-threonyl)piperidin-4-yl)-2-(trifluoromethyl)benzoate (0.150 g, 0.16 mmol) in a mixture of THF-water (3:1; 4 mL) was added lithium hydroxide monohydrate (0.020 g, 0.49 mmol) at room temperature and the resulting reaction mixture stirred for 6h at room temperature. Volatiles were distilled off under reduced pressure, obtained crude was diluted with water (40 mL) and it was extracted with diethyl ether (50 mL x 2) to remove unwanted impurities. Aqueous part was acidified (pH ~ 2-3) with an aqueous solution of 1N HCl and was extracted with ethyl acetate (30 mL × 3). Combined organic extracts were wash with brine (20 mL), dried over anhydrous Na2SO4and concentrated under reduced pressure to get a crude product. The crude product was purified by prep-HPLC, 0.1% formic acid in water-acetonitrile as gradient, to afford 5-(1-(O-((2-oxabicyclo[2.2.2]octan-4-yl)methyl)-N-((S)-6-(5- hydroxypyrazine-2-carbonyl)-2-(1-(trifluoromethyl)cyclopropane-1carbonyl)-2,6-diazaspiro [3.4] octane-8-carbonyl)-D-threonyl)piperidin-4-yl)-2-(trifluoromethyl)benzoic acid (0.009 g, 6%) as a white solid.1H-NMR (400 MHz, MeOH-d4) δ 8.30-8.10 (m, 1H), 8.10-7.95 (m, 2H), 7.75-7.60 (m, 2H), 7.59-7.49 (m, 1H), 5.00-4.90 (m, 1H; merged in moisture from MeOH-d4),4.71-4.62 (m, 2H), 4.48-4.33 (m, 2H), 4.25-2.19 (m 3H), 4.15-4.08 (m, 2H), 3.75 (br. s, 4H), 3.50- 3.30 (m, 2H, merged in DMSO-d6), 3.21-2.62 (m, 3H), 2.90-2.77 (m, 1H), 2.12-1.91 (m, 4H), 1.80-1.43 (m, 8H), 1.31-1.15 (m, 8H); MS: [MH]+895.6.

[0257] Synthesis of 2-(1-(O-((2-oxabicyclo[2.2.2]octan-4-yl)methyl)-N-((S)-6-(5- hydroxypyrazine-2-carbonyl)-2-(1-(trifluoromethyl)cyclopropane-1-carbonyl)-2,6- diazaspiro[3.4]octane-8-carbonyl)-L-threonyl) piperidin-4-yl)-5-(trifluoromethyl)benzoic acid (I-1)

[0258] Synthesis of (R)-3-((S)-6-benzyl-2,6-diazaspiro[3.4]octane-8-carbonyl)-4- phenyloxazolidin-2-one: To a stirred solution of tert-butyl (S)-6-benzyl-8-((R)-2-oxo-4- phenyloxazolidine-3-carbonyl)-2,6-diazaspiro[3.4]octane-2-carboxylate (8.0 g, 16.28 mmol) in DCM (40 mL) was added TFA (16 mL) drop-wise at 00C under nitrogen and the resulting reaction mixture was stirred at room temperature for 2h. [An identical batch (8.0 g) was combined with this batch prior to work-up]. Reaction mixture was concentrated under reduced pressure, obtained crude product was diluted with ice water (200 mL), basified (pH~ 8-9) with an aqueous solution of saturated NaHCO3and was extracted with DCM (300 mL × 3). Combined organic extracts were dried over anhydrous Na2SO4and concentrated under reduced pressure to afforded (R)-3-((S)-6- benzyl-2,6-diazaspiro[3.4]octane-8-carbonyl)-4-phenyloxazolidin-2-one (11.0 g, quantitative(TFA salt); crude) as an oil, which was used in next step without further purification. MS: [MH]+392.5.

[0259] Synthesis of (R)-3-((S)-6-benzyl-2-(1-(trifluoromethyl)cyclopropane-1-carbonyl)-2,6- diazaspiro[3.4]octane-8-carbonyl)-4-phenyloxazolidin-2-one: To a stirred solution of 1- (trifluoromethyl) cyclopropane-1-carboxylic acid (6.00 g, 38.96 mmol) in DCM (60.0 mL) was added DIPEA (54.2 mL, 311.68 mmol) and HATU (22.20 g, 58.44 mmol) at 00C under nitrogen. After 10 minutes of stirring at the same temperature, was added(R)-3-((S)-6-benzyl-2,6- diazaspiro[3.4]octane-8-carbonyl)-4-phenyloxazolidin-2-one (12.18 g, 31.16 mmol) and stirring was continued for 1h at room temperature. Reaction mixture was slowly poured into ice water (100 mL) and was extracted with ethyl acetate (100 mL × 3). Combined organic extracts were wash with brine (100 mL), dried over anhydrous Na2SO4and concentrated under reduced pressure to get a crude product, which was purified by reverse phase (C-18) silica gel column chromatography using acetonitrile-water=0:1→6:1 as gradient, to afford (R)-3-((S)-6-benzyl-2-(1- (trifluoromethyl)cyclopropane-1-carbonyl)-2,6-diazaspiro [3.4] octane-8-carbonyl)-4- phenyloxazolidin -2-one (6.50 g, 80%) as an off white solid. MS: [MH]+528.5.

[0260] Synthesis of (R)-4-phenyl-3-((S)-2-(1-(trifluoromethyl)cyclopropane-1-carbonyl)-2,6- diazaspiro[3.4]octane-8-carbonyl)oxazolidin-2-one: To a stirred solution of (R)-4-phenyl-3- ((S)-2-(1-(trifluoromethyl)cyclopropane-1-carbonyl)-2,6-diazaspiro[3.4]octane-8- carbonyl)oxazolidin-2-one (4.00 g, 7.59 mmol) in a mixture of ethyl acetate-methanol (1:1, 20 mL) was added 10% Pd in activated carbon (2.0 g) at room temperature under nitrogen. The resulting reaction mixture hydrogenated under balloon pressure at room temperature for 8h. [An identical batch (4.0 g) was performed, in parallel and mixed together prior to work-up]. Combined reaction mixtures were filtered through a celite bed, washed the bed with ethyl acetate (200 mL) and collected filtrates were concentrated under reduced pressure to afforded (R)-3-((S)-2-((S)-2,2- dimethylcyclopropane-1-carbonyl)-2,6-diazaspiro[3.4]octane-8-carbonyl)-4-phenyloxazolidin-2- one (7.60 g, quantitative; crude) as an off white solid. MS: [MH]+438.3.

[0261] Synthesis of (R)-3-((S)-6-(5-hydroxypyrazine-2-carbonyl)-2-(1- (trifluoromethyl)cyclopropane-1-carbonyl)-2,6-diazaspiro[3.4]octane-8-carbonyl)-4- phenyloxazolidin-2-one: To a stirred solution 5-hydroxypyrazine-2-carboxylic acid (1.90 g, 13.57mmol) in DMF were added DIPEA (7.17 mL, 40.71 mmol) and HATU (7.73 g, 20.35 mmol) at 00C under nitrogen. After 10 minutes of stirring at the same temperature, was added (R)-3-((S)-2- ((S)-2,2-dimethylcyclopropane-1-carbonyl)-2,6-diazaspiro [3.4] octane-8-carbonyl)-4- phenyloxazolidin-2-one (4.10 g, 9.49 mmol) and stirring was continued for 4h at same temperature. Reaction mixture was slowly poured into ice water (100 mL) and extracted with ethyl acetate (100 mL × 3). Combined organic extracts were wash with brine (100 mL), dried over anhydrous Na2SO4and concentrated under reduced pressure. The resulting crude was purified by reverse phase (C-18) silica gel column chromatography using acetonitrile-water=0:1→3:1 as gradient, to afford (R)-3-((S)-6-(5-hydroxypyrazine-2-carbonyl)-2-(1- (trifluoromethyl)cyclopropane-1-carbonyl)-2,6-diazaspiro [3.4] octane -8-carbonyl)-4- phenyloxazolidin -2-one as an off white solid (1.9 g, 25%) as an oil. MS: [MH]+560.3.

[0262] Synthesis of (S)-6-(5-hydroxypyrazine-2-carbonyl)-2-(1- (trifluoromethyl)cyclopropane-1-carbonyl)-2,6-diazaspiro[3.4]octane-8-carboxylic acid: To a stirred solution of (R)-3-((S)-6-(5-hydroxypyrazine-2-carbonyl)-2-(1- (trifluoromethyl)cyclopropane-1-carbonyl)-2,6-diazaspiro[3.4]octane-8-carbonyl)-4- phenyloxazolidin-2-one (0.100 g, 0.17 mmol) in THF (1 mL) was added an aqueous 30% H2O2(1 mL) at 00C. After stirring at room temperature for 2h, was added an aqueous (0.2 mL) solution of lithium hydroxide monohydride (0.012 g, 0.286 mmol) into the reaction mixture and the resulting mixture was stirred at same temperature for 1h. [another batch of 0.500 g was performed and mixed together prior to work-up]. Combined mixtures were diluted with water (20 mL) and was extracted with ethyl acetate (50 mL x 2) to remove unwanted organic impurities. The aqueous layer was acidified (pH ~ 3-4) with formic acid and the resulting solution extracted with 20% IPA in chloroform (50 mL x 2). Combined organic extracts were washed with brine (300 mL), dried over anhydrous Na2SO4and concentrated under reduced pressure to get (S)-6-(5-hydroxypyrazine-2- carbonyl)-2-(1-(trifluoromethyl)cyclopropane-1-carbonyl)-2,6-diazaspiro [3.4] octane-8- carboxylic acid (0.300 g, 67%; crude) as a brown solid. MS: [MH]+415.3.

[0263] Synthesis of Ethyl 2-(1-(o-((2-oxabicyclo[2.2.2]octan-4-yl)methyl)-N-((S)-6-(5- hydroxypyrazine-2-carbonyl)-2-(1-(trifluoromethyl)cyclopropane-1-carbonyl)-2,6- diazaspiro[3.4]octane-8-carbonyl)-L-threny l)pipe ridin-4-yl)-5-(trifluoromethyl)benzoate: To a stirred solution of (S)-6-(5-hydroxypyrazine-2-carbonyl)-2-(1-(trifluoromethyl)cyclopropane-1-carbonyl)-2,6-diazaspiro [3.4]octane-8-carboxylic acid (0.115 g, 0.27 mmol) in DCM (2.0 mL) were added ethyl 2-(1-(O-((2-oxabicyclo[2.2.2]octan-4-yl)methyl)- L-threonyl)piperidin-4-yl)-5-(trifluoromethyl) benzoate (0.146 g, 0.27 mmol) and DCC (0.114 g, 0.555 mmol) at 00C under nitrogen. The resulting reaction mixture stirred for 2h at room temperature. Reaction mixture was slowly poured into ice water (50 mL) and was extracted with DCM (50 mL × 3). Combined organic extracts were washed with brine (20 mL), dried over anhydrous Na2SO4and concentrated under reduced pressure to get a crude product. The crude product was purified by column chromatography on silica gel (DCM-MeOH = 0.8:9.2) to afford methyl ethyl 2-(1-(o-((2-oxabicyclo[2.2.2]octan-4-yl)methyl)-N-((S)-6-(5-hydroxypyrazine-2- carbonyl)-2-(1-(trifluoromethyl)cyclopropane-1-carbonyl)-2,6-diazaspiro[3.4]octane-8- carbonyl)-L-threonyl)piperidin-4-yl)-5-(trifluoromethyl) benzoate (0.060 g, 23%) as an off white solid. MS: [MH]+923.6.

[0264] Synthesis of 2-(1-(O-((2-oxabicyclo[2.2.2]octan-4-yl)methyl)-N-((S)-6-(5- hydroxypyrazine-2-carbonyl)-2-(1-(trifluoromethyl)cyclopropane-1-carbonyl)-2,6- diazaspiro[3.4]octane-8-carbonyl)-L-threonyl) piperidin-4-yl)-5-(trifluoromethyl)benzoic acid: To a stirred solution of ethyl 2-(1-(o-((2-oxabicyclo[2.2.2]octan-4-yl)methyl)-N-((S)-6-(5- hydroxypyrazine-2-carbonyl)-2-(1-(trifluoromethyl)cyclopropane-1-carbonyl)-2,6-diazaspiro [3.4] octane-8-carbonyl)-L-threonyl) piperidin-4-yl)-5-(trifluoromethyl)benzoate (0.150 g, 0.16 mmol) in a mixture of THF-water (3:1; 2 mL) and methanol (0.3 mL) was added an aqueous (0.2 mL) solution of LiOH.H2O (0.020 g, 0.48 mmol) at 00C and stirred for 3h at room temperature. Volatiles were distilled off under reduced pressure, obtained crude was acidified (pH ~ 4) with an aqueous solution of 1N HCl and was extracted with ethyl acetate (50 mL × 3). Combined organic extracts washed with brine (20 mL), dried over anhydrous Na2SO4and concentrated under reduced pressure to get a crude product. The crude product was purified by prep-HPLC, 0.1% formic acid in water-acetonitrile as gradient, to afforded 2-(1-(O-((2-oxabicyclo[2.2.2]octan-4-yl)methyl)-N- ((S)-6-(5-hydroxypyrazine-2-carbonyl)-2-(1-(trifluoromethyl) cyclopropane-1-carbonyl)-2,6- diazaspiro [3.4] octane-8-carbonyl)-L-threonyl)piperidin-4-yl)-5-(trifluoromethyl) benzoic acid (0.025 g, 17%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.43-8.31 (m, 1H), 8.09-7.89 (m, 2H), 7.80-7.78 (m, 1H), 7.70-7.59 (m, 1H), 7.50-7.41 (m, 1H), 4.92-4.75 (m, 2H), 4.59-4.53 (m, 1H), 4.40-4-30 (m, 1H), 4.30-4.20 (s, 1H), 4.12-4.07 (m, 2H), 3.95-3.90 (m, 3H), 3.87-3.78(m, 3H), 3.62 (s, 2H), 3.55 (s, 4H), 3.18-3.11 (m, 2H), 3.05-2.98 (m, 1H), 1.81 (br. s, 4H), 1.53 (br. s, 5H), 1.42-1.35 (m, 2H), 1.23-1.14 (m, 4H), 1.10-0.98 (m, 3H). MS: [MH]+895.7.

[0265] Synthesis of 4-(1-(O-((2-Oxabicyclo[2.2.2]octan-4-yl)methyl)-N-((S)-6-(1-(4- (trifluoromethyl)benzyl)-1H-pyrazole-4-carbonyl)-2-(1-(trifluoromethyl)cyclopropane-1- carbonyl)-2,6-diazaspiro[3.4]octane-8-carbonyl)-L-threonyl)piperidin-4-yl)-2- hydroxybenzoic acid (I-81)

[0266] Synthesis of tert-Butyl 4-(3-hydroxy-4-(methoxycarbonyl)phenyl)-3,6- dihydropyridine-1(2H)-carboxylate: To a stirred solution of methyl 4-bromo-2- hydroxybenzoate (1.0 g, 4.34 mmol) in a DMF (7.0 mL) were added tert-butyl 4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.34 g, 4.34 mmol) and K2CO3(1.79 g, 13.04 mmol) at room temperature. The reaction mixture was degassed (purging with nitrogen) for 20 min followed by addition of Pd(PPh3)4(0.250 g, 0.21 mmol) and stirred at 1000C for 16h. [Two more batched of 1.0 g each were carried out in parallel and mixed all together prior to work-up]. Combined reaction mixture was cool to room temperature, diluted with water (100 mL) and was extracted with diethyl ether (100 mL × 3). Combined organic extracts were washed with brine (200 mL), dried over anhydrous Na2SO4and concentrated under reduce pressure. Obtained crude was purified by silica gel column chromatography, using ethyl acetate- hexane = 0:1→ 0.7:9.3 as gradient, to afford tert-butyl 4-(3-hydroxy-4-(methoxycarbonyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate (1.1 g, 25%) as a colourless liquid. MS: [MH-56]+278.3.

[0267] Synthesis of Tert-butyl 4-(3-hydroxy-4-(methoxycarbonyl)phenyl)piperidine-1- carboxylate: To a stirred solution of tert-butyl 4-(3-hydroxy-4-(methoxycarbonyl)phenyl)-3,6- dihydropyridine-1(2H)-carboxylate (1.1 g, 3.30 mmol) in a methanol (10 mL) was added 10% Pd in activated carbon (0.550 g) at room temperature under nitrogen and the resulting mixture was hydrogenated under balloon pressure at the same temperature for 2h. The reaction mixture was filter through a celite bed, washed the bed with methanol (100 mL) and collected filtrates were concentrated under reduced pressure to afforded tert-butyl 4-(3-hydroxy-4- (methoxycarbonyl)phenyl)piperidine-1-carboxylate (0.900 g, 81%; crude) as a colourless oil. MS: [MH-56]+280.3.

[0268] Synthesis of Methyl 2-hydroxy-4-(piperidin-4-yl)benzoate: To a stirred solution of tert- butyl 4-(3-hydroxy-4-(methoxycarbonyl)phenyl)piperidine-1-carboxylate (1.50 g, 4.47 mmol) in DCM (10 mL) was added 4M HCl in dioxane (7 mL) at 00C and stirred at room temperature for 1h. The reaction mixture was concentrated under reduced pressure to obtained crude product which was purified by trituration using n-pentane to afford methyl 2-hydroxy-4-(piperidin-4-yl)benzoate (1.20 g, quantitative; crude) as an off-white solid. MS: [MH]+236.4.

[0269] Synthesis of Methyl 4-(1-(O-((2-oxabicyclo[2.2.2]octan-4-yl)methyl)-N-(((4- nitrobenzyl)oxy)carbonyl)-L-threonyl)piperidin-4-yl)-2-hydroxybenzoate: To a stirred solution of O-((2-oxabicyclo[2.2.2]octan-4-yl)methyl)-N-(((4-nitrobenzyl)oxy)carbonyl)-L- threonine (1.2 g, 2.84 mmol) in DCM (10.0 mL), were added DIPEA (1.1 g, 8.52 mmol) and HATU (2.1 g, 5.68 mmol) at 00C under nitrogen. After 10 minutes of stirring at the same temperature, was added methyl 2-hydroxy-4-(piperidin-4-yl)benzoate (1.0 g, 4.26 mmol) and stirring was continued for 1h at room temperature. The reaction mixture was slowly poured into ice water (70 mL) and was extracted with dichloromethane (100 mL × 3), dried over anhydrous Na2SO4and concentrated under reduced pressure to get a crude product. The crude product was purified by silica gel column chromatography, using ethyl acetate-hexane = 0:1→ 6:4 as gradient, to afford methyl 4-(1-(O-((2-oxabicyclo[2.2.2]octan-4-yl)methyl)-N-(((4-nitrobenzyl)oxy)carbonyl)-L-threonyl)piperidin-4-yl)-2-hydroxybenzoate (0.800 g, 44%) as a colorless liquid. MS: [MH]+640.5.

[0270] Synthesis of Methyl 4-(1-(O-((2-oxabicyclo[2.2.2]octan-4-yl)methyl)-L- threonyl)piperidin-4-yl)-2-hydroxybenzoate: To a stirred solution of methyl 4-(1-(O-((2- oxabicyclo[2.2.2]octan-4-yl)methyl)-N-(((4-nitrobenzyl)oxy)carbonyl)-L-threonyl)piperidin-4- yl)-2-hydroxybenzoate (0.750 g, 1.17 mmol) in methanol (5.0 mL) was added 10% Pd in activated carbon (0.350 g) at room temperature under nitrogen and the resulting mixture was hydrogenated under balloon pressure at the same temperature for 1h. The reaction mixture filtered through celite bed, washed the bed with methanol (50 mL) and collected filtrates were concentrated under reduced pressure. The crude product was purify by silica gel column chromatography, using MeOH-DCM = 0:1→ 1.5:8.5 to afford methyl 4-(1-(O-((2-oxabicyclo[2.2.2]octan-4-yl)methyl)- L-threonyl)piperidin-4-yl)-2-hydroxybenzoate (0.330 g, 61%) as a colour less liquid. MS: [MH]+461.4

[0271] Synthesis of 1-(4-(Trifluoromethyl)benzyl)-1H-pyrazole-4-carboxylic acid

[0272] Synthesis of Methyl 1-(4-(trifluoromethyl)benzyl)-1H-pyrazole-4-carboxylate: To a stirred solution of methyl 1H-pyrazole-4-carboxylate (20.0 g, 158.70 mmol) in DMF (200 mL) were added K2CO3(54.70 g, 396.8 mmol) and 1-(chloromethyl)-4-(trifluoromethyl)benzene (36.90 g, 190.41 mmol) sequentially at room temperature and the resulting mixture was stirred at 90 °C for 2h. Reaction mixture slowly poured into ice water (500 mL), during which a solid was precipitated. Reaction mixture was filtered over a celite bed, obtained residue was washed with cold water and dried under high vacuum to afford methyl 1-(4-(trifluoromethyl)benzyl)-1H- pyrazole-4-carboxylate (30.0 g, 92%; crude) as a white solid. MS: [MH]+285.3.

[1000] Synthesis of 1-(4-(Trifluoromethyl)benzyl)-1H-pyrazole-4-carboxylic acid: To a stirred solution of methyl 1-(4-(trifluoromethyl)benzyl)-1H-pyrazole-4-carboxylate (15.0 g, 52.81 mmol) in a mixture of THF-water (3:1; 150 mL) was added lithium hydroxide monohydrate (6.65 g, 158.4 mmol) at room temperature and stirred for 3h at the same temperature. Reaction mixture was concentrated under reduced pressure, obtained crude was diluted with water (100 mL) and was extracted with ethyl acetate (100 mL x 2) to remove unwanted impurities. Aqueous part was acidified (pH ~ 3-4) with 1N HCl aqueous solution and the resulting precipitate collected by filtration. Crude residue was washed with cold water until the pH of the filtrate became neutral (pH ~ 6-7) and dried under high vacuum to afford 1-(4-(trifluoromethyl)benzyl)-1H-pyrazole-4- carboxylic acid (12.0 g, quant.; crude) as a white solid. MS: [MH]+271.3.

[1001] Synthesis of 4-(1-(O-((2-Oxabicyclo[2.2.2]octan-4-yl)methyl)-N-((S)-6-(1-(4- (trifluoromethyl)benzyl)-1H-pyrazole-4-carbonyl)-2-(1-(trifluoromethyl)cyclopropane-1- carbonyl)-2,6-diazaspiro[3.4]octane-8-carbonyl)-L-threonyl)piperidin-4-yl)-2- hydroxybenzoic acid (I-81)

[0273] Synthesis of (R)-4-Phenyl-3-((S)-6-(1-(4-(trifluoromethyl)benzyl)-1H-pyrazole-4- carbonyl)-2-(1-(trifluoromethyl)cyclopropane-1-carbonyl)-2,6-diazaspiro[3.4]octane-8- carbonyl)oxazolidin-2-one: To a stirred solution of 1-(4-(trifluoromethyl)benzyl)-1H-pyrazole- 4-carboxylic acid (6.2 g, 22.96 mmol) in DMF (60 mL) were added DIPEA (8.88 g, 68.88 mmol) and HATU (13.08 g, 34.44 mmol) at 00C under nitrogen. After 10 minutes of stirring at the same temperature, was added (R)-4-phenyl-3-((S)-2-(1-(trifluoromethyl)cyclopropane-1-carbonyl)-2,6-diazaspiro[3.4]octane-8 carbonyl)oxazolidin-2-one (12.04 g, 27.55 mmol) and stirred at room temperature for another 1h. The resulting reaction mixture was slowly poured into ice water (150 mL) and was extracted with ethyl acetate (500 mL × 2). Combined organic extracts were washed with brine (200 mL) and dried over anhydrous Na2SO4,and concentrated under reduced pressure to get a crude product. The crude product was purified by silica gel column chromatography, using MeOH-DCM = 0:1→ 0.5:9.5 as gradient, to afford (R)-4-phenyl-3-((S)-6-(1-(4- (trifluoromethyl)benzyl)-1H-pyrazole-4-carbonyl)-2-(1-(trifluoromethyl)cyclopropane-1- carbonyl)-2,6-diazaspiro[3.4]octane-8-carbonyl)oxazolidin-2-one (8.0 g, 82%) as a yellow solid. MS: [MH]+690.3.

[0274] Synthesis of (S)-6-(1-(4-(Trifluoromethyl)benzyl)-1H-pyrazole-4-carbonyl)-2-(1 (trifluoromethyl)cyclopropane-1-carbonyl)-2,6-diazaspiro[3.4]octane-8-carboxylic acid: To a stirred solution of (R)-4-phenyl-3-((S)-6-(1-(4-(trifluoromethyl)benzyl)-1H-pyrazole-4- carbonyl)-2-(1-(trifluoromethyl)cyclopropane-1-carbonyl)-2,6-diazaspiro[3.4]octane-8- carbonyl)oxazolidin-2-one (2.0 g, 2.90 mmol) in a mixture of THF-water (10:2; 12 mL) was added 30% aqueous H2O2(10 mL) at 00C and the resulting reaction mixture was stirred at room temperature for 2h. Lithium hydroxide monohydrate (0.230 g, 5.51 mmol) was added into the reaction solution at 00C and stirring was further continued at room temperature for 10 minutes. [One more batch (2.5 g) was performed and combined with the present batch prior to work-up]. Combined mixtures were backwashed with ethyl acetate (30 mL x 2), separated aqueous layer was acidified (pH ~ 4) with formic acid and was extracted with 20% MeOH in DCM (100 mL × 4). Collected organic parts were dried over anhydrous Na2SO4and concentrated under reduced pressure to get (S)-6-(1-(4-(trifluoromethyl)benzyl)-1H-pyrazole-4-carbonyl)-2-(1- (trifluoromethyl)cyclopropane-1-carbonyl)-2,6-diazaspiro[3.4]octane-8-carboxylic acid (3.1 g, 87%; crude) as an off white solid. MS: [MH]+545.2.

[0275] Synthesis of Methyl 4-(1-(O-((2-oxabicyclo[2.2.2]octan-4-yl)methyl)-N-((S)-6-(1-(4- (trifluoromethyl)benzyl)-1H-pyrazole-4-carbonyl)-2-(1-(trifluoromethyl)cyclopropane-1- carbonyl)-2,6-diazaspiro[3.4]octane-8-carbonyl)-L-threonyl)piperidin-4-yl)-2- hydroxybenzoate: To a stirred solution of (S)-6-(1-(4-(trifluoromethyl)benzyl)-1H-pyrazole-4- carbonyl)-2-(1-(trifluoromethyl)cyclopropane-1-carbonyl)-2,6-diazaspiro[3.4]octane-8- carboxylic acid (0.250 g, 0.45 mmol) in DCM (5 mL) were added methyl 4-(1-(O-((2-oxabicyclo[2.2.2]octan-4-yl)methyl)-L-threonyl)piperidin-4-yl)-2-hydroxybenzoate (0.310 g, 0.68 mmol) and DCC (0.190 g, 0.91 mmol) sequentially at 00C under nitrogen and the resulting mixture stirred at room temperature for 2h. Reaction mixture was slowly poured into ice water (50 mL) and was extracted with DCM (50 mL × 3). Combined organic extracts were wash with brine (20 mL) and dried over anhydrous Na2SO4and concentrated under reduced pressure to get a crude product. The crude product was purified by silica gel column chromatography, using MeOH-DCM = 0:1 →1:9 as gradient, to afford methyl 4-(1-(O-((2-oxabicyclo[2.2.2]octan-4-yl)methyl)-N-((S)- 6-(1-(4-(trifluoromethyl)benzyl)-1H-pyrazole-4-carbonyl)-2-(1-(trifluoromethyl)cyclopropane-1- carbonyl)-2,6-diazaspiro[3.4]octane-8-carbonyl)-L-threonyl)piperidin-4-yl)-2-hydroxybenzoate (0.400 g, 57%) as an off-white solid. MS: [MH]+987.6.

[0276] Synthesis of 4-(1-(O-((2-Oxabicyclo[2.2.2]octan-4-yl)methyl)-N-((S)-6-(1-(4- (trifluoromethyl)benzyl)-1H-pyrazole-4-carbonyl)-2-(1-(trifluoromethyl)cyclopropane-1- carbonyl)-2,6-diazaspiro[3.4]octane-8-carbonyl)-L-threonyl)piperidin-4-yl)-2- hydroxybenzoic acid: To a stirred solution of methyl 4-(1-(O-((2-oxabicyclo[2.2.2]octan-4- yl)methyl)-N-((S)-6-(1-(4-(trifluoromethyl)benzyl)-1H-pyrazole-4-carbonyl)-2-(1- (trifluoromethyl)cyclopropane-1-carbonyl)-2,6-diazaspiro[3.4]octane-8-carbonyl)-L- threonyl)piperidin-4-yl)-2-hydroxybenzoate (0.350 g, 0.35 mmol) in a mixture of THF-water (3.5:1.5; 5 mL) was added lithium hydroxide monohydrate (0.044 g, 1.06 mmol) at room temperature and the resulting reaction mixture was stirred at 600C for 8h. After cooling to room temperature, the reaction mass was backwashed with diethyl ether (50 mL x 2), separated aqueous layer was acidified (pH ~ 2-3) with 1N HCl solution and was extracted with ethyl acetate (50 mL × 3). Combined organic extracts were dried over anhydrous Na2SO4and concentrated under reduced pressure to get a crude product, which was purified by prep-HPLC, 0.1% formic acid in water-acetonitrile as gradient, to afford 4-(1-(O-((2-oxabicyclo[2.2.2]octan-4-yl)methyl)-N-((S)- 6-(1-(4-(trifluoromethyl)benzyl)-1H-pyrazole-4-carbonyl)-2-(1-(trifluoromethyl)cyclopropane-1- carbonyl)-2,6-diazaspiro[3.4]octane-8-carbonyl)-L-threonyl)piperidin-4-yl)-2-hydroxybenzoic acid (0.070, 20%) as a white solid.1H-NMR (400 MHz, DMSO-d6) δ 13.91 (br, 1H), 11.22 (br, 1H), 8.43-8.39 (m, 2H), 7.87-7.83 (d, J=16.0 Hz, 1H), 7.73-7.71 (m, 3H), 7.44-7.43 (d, J=6.4 Hz, 2H),6.79 (brs, 2H), 5.48 (s, 2H), 4.88-4.83 (m, 1H), 4.52-4.50 (m, 1H), 4.39-3.41 (m, 14H), 3.23- 2.67 (m, 4H), 2.50 (m, 4H; merged in DMSO-d6), 1.93-1.69 (m, 3H), 1.54-1.01 (m, 13H). MS: [MH]+973.6.

[0277] Synthesis of 2-(piperidin-4-yl)thiazole

[0278] Synthesis of tert-Butyl 4-(thiazol-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate: To a stirred solution of 2-bromothiazole (4.0 g, 24.53 mmol) in a mixture of dioxane and water (4:1, 100 mL) were added tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6- dihydropyridine-1(2H)-carboxylate (9.09 g, 29.44 mmol) and K2CO3(10.15 g, 73.61 mmol) sequentially at room temperature. The reaction mixture was degassed (purging with nitrogen) for 20 min followed by the addition of PdCl2(dppf) (1.80 g, 2.43 mmol) and the reaction mixture was heated at 900C for 4h. After cooling to room temperature, reaction was diluted with water (200 mL) and was extracted with diethyl ether (100 mL × 3). Collected organic extracts were washed with brine (200 mL), dried over anhydrous Na2SO4and concentrated under reduce pressure. The crude product was purified by silica gel column chromatography, using ethyl acetate-hexane = 0:1→0.7:9.3 as gradient, to afford tert-butyl 4-(thiazol-2-yl)-3,6-dihydropyridine-1(2H) (5.0 g, 80%) as a colourless oil. MS: [(M-56)+H]+267.1.

[0279] Synthesis of tert-Butyl 4-(thiazol-2-yl)piperidine-1-carboxylate: To a stirred solution of tert-butyl 4-(thiazol-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (3.0 g, 11.27 mmol) in a methanol (30 mL) was added 10% Pd in activated carbon (1.3 g) at room temperature under nitrogen and the resulting mixture was hydrogenated under balloon pressure at the same temperature for 2h. Reaction mixture was filter through a celite bed, washed the bed with methanol (100 mL) and collected filtrates were concentrated under reduced pressure to afford tert-butyl 4- (thiazol-2-yl)piperidine-1-carboxylate (2.8 g, 92%) as a colorless oil. MS: [(M-100)+H]+169.1.

[0280] Synthesis of 2-(Piperidin-4-yl)thiazole: To a stirred solution of tert-butyl 4-(thiazol-2- yl)piperidine-1-carboxylate (1.5 g, 5.59 mmol) in DCM (10.0 mL) was added 4M HCl in dioxane(9.0 mL) at 00C and stirred the solution at room temperature for 1h. Reaction mixture was concentrated under reduced pressure to obtained crude product, which was purified by trituration using n-pentane, to afford 2-(piperidin-4-yl)thiazole hydrochloride (1.4 g, quantitative) as an off- white solid. MS: [MH]+169.1.

[0281] Synthesis of afforded (S)-N-((2S,3R)-1-oxo-3-((tetrahydro-2H-pyran-4-yl)methoxy)- 1-(4-(thiazol-2-yl)piperidin-1-yl)butan-2-yl)-6-(1-(4-(trifluoromethyl)benzyl)-1H-pyrazole- 4-carbonyl)-2-(1-(trifluoromethyl)cyclopropane-1-carbonyl)-2,6-diazaspiro[3.4]octane-8- carboxamide (I-79)

[0282] Synthesis of 2-methyl 1-(4-nitrobenzyl) (2S,3S)-3-methylaziridine-1,2-dicarboxylate mentioned under Methyl 2-(1-(O-((2-oxabicyclo[2.2.2]octan-4-yl)methyl)-L-threonyl)piperidin-4- yl)-5-(trifluoromethyl)benzoate.

[0283] Synthesis of Methyl N-(((4-nitrobenzyl)oxy)carbonyl)-O-((tetrahydro-2H-pyran-4- yl)methyl)-L-threoninate: To a stirred solution of 2-methyl 1-(4-nitrobenzyl) (2S,3S)-3- methylaziridine-1,2-dicarboxylate (3.0 g, 10.20 mmol) in CHCl3(10 mL) was added (tetrahydro- 2H-pyran-4-yl)methanol (1.42 g, 12.24 mmol) at 00C under nitrogen. After 5 min of stirring at the same temperature, was added BF3-Et2O (2.89 g, 20.40 mmol) drop-wise- into the reaction mass and allowed to stirred at room temperature for 3h. [Another identical batch (3.0 g) was carried out in parallel and mixed together prior to work-up]. Combined reaction mixtures were concentrated under reduced pressure to get crude product, which was purified by silica gel columnchromatography using EtOAc-hexane = 3:7→4:6 as gradient, to afforded methyl N-(((4- nitrobenzyl)oxy)carbonyl)-O-((tetrahydro-2H-pyran-4-yl)methyl)-L-threoninate (5.1 g, 60%) as a yellow liquid. MS: MH]+ 411.3.

[0284] Synthesis of N-(((4-nitrobenzyl)oxy)carbonyl)-O-((tetrahydro-2H-pyran-4- yl)methyl)-L-threonine: To a stirred solution of methyl N-(((4-nitrobenzyl)oxy)carbonyl)-O- ((tetrahydro-2H-pyran-4-yl)methyl)-L-threoninate (3.4 g, 8.29 mmol) in THF (20 mL) was added an aqueous (6 mL) solution of LiOH.H2O (1.39 g, 33.17 mmol) at room temperature and allowed to stir for 5h. [Another batch of 2.7g was performed in parallel and mixed together prior to work- up]. Combined reaction mixtures was back washed by diethyl ether (200 mL), separated aqueous layer was acidified (pH = 2-3) with an aqueous solution of 1N HCl and was extracted with ethyl acetate (200 mL × 2). Collected organic extracts were dried over anhydrous Na2SO4and concentrated under reduced pressure to afforded N-(((4-nitrobenzyl)oxy)carbonyl)-O- ((tetrahydro-2H-pyran-4-yl)methyl)-L-threonine (4.5 g, 91%; crude) as a yellow oil, which was used in next step without purification. MS: [MH]+ 397.3.

[0285] Synthesis of 4-Nitrobenzyl ((2S,3R)-1-oxo-3-((tetrahydro-2H-pyran-4-yl)methoxy)-1- (4-(thiazol-2-yl)piperidin-1-yl)butan-2-yl)carbamate: To a stirred solution of N-(((4- nitrobenzyl)oxy)carbonyl)-O-((tetrahydro-2H-pyran-4-yl)methyl)-L-threonine (1.48g, 3.73 mmol) in DCM (10 mL), was added DIPEA (1.36 g, 10.605 mmol) at room temperature. The resulting reaction mixture cooled at 00C followed by addition of HATU (2.13 g, 5.60 mmol). After additional stirring for 10 min at the same temperature, was added 2-(piperidin-4-yl)thiazole (0.940 g, 5.60 mmol) was added at 00C temperature and stirring was continued at room temperature for 3h. Reaction mixture was diluted with water (200 mL) and was extracted with DCM (200 × 2 mL). Combined organic extracts were dried over anhydrous Na2SO4and concentrated under reduced pressure to get a crude product, which was purified by silica gel column chromatography using MeOH-DCM =0:1→0.5:9.5 as gradient, to afforded 4-nitrobenzyl ((2S,3R)-1-oxo-3- ((tetrahydro-2H-pyran-4-yl)methoxy)-1-(4-(thiazol-2-yl)piperidin-1-yl)butan-2-yl)carbamate (1.30 g, 67%) as light yellow liquid. MS: [MH]+547.3.

[0286] Synthesis of (2S,3R)-2-amino-3-((tetrahydro-2H-pyran-4-yl)methoxy)-1-(4-(thiazol- 2-yl)piperidin-1-yl)butan-1-one: To a stirred solution of 4-nitrobenzyl ((2S,3R)-1-oxo-3-((tetrahydro-2H-pyran-4-yl)methoxy)-1-(4-(thiazol-2-yl)piperidin-1-yl)butan-2-yl)carbamate (1.3 g, 2.38 mmol) in methanol (10 mL) was added Pd / C (0.600 g) at room temperature under nitrogen. The reaction mixture was degassed (purging with nitrogen) for 5 min followed by hydrogenated under balloon pressure at room temperature. Reaction mixture was filtered through celite bed, washed the bed with MeOH (200 mL) and collected filtrates were concentrated under reduced pressure to get crude product. The resulting crude was purified by silica gel column chromatography using DCM-MeOH =0.5:9.5→0.9:9.1 as gradient, to afforded (2S,3R)-2-amino- 3-((tetrahydro-2H-pyran-4-yl)methoxy)-1-(4-(thiazol-2-yl)piperidin-1-yl)butan-1-one (0.450 g, 51%) as yellow liquid. MS: [MH]+ 368.3.

[0287] Synthesis of (S)-N-((2S,3R)-1-oxo-3-((tetrahydro-2H-pyran-4-yl)methoxy)-1-(4- (thiazol-2-yl)piperidin-1-yl)butan-2-yl)-6-(1-(4-(trifluoromethyl)benzyl)-1H-pyrazole-4- carbonyl)-2-(1-(trifluoromethyl)cyclopropane-1-carbonyl)-2,6-diazaspiro[3.4]octane-8- carboxamide: To a stirred solution of (2S,3R)-2-amino-3-((tetrahydro-2H-pyran-4-yl)methoxy)- 1-(4-(thiazol-2-yl)piperidin-1-yl)butan-1-one (0.390 g, 0.96 mmol) in DCM (5 mL) was added (S)-6-(1-(4-(trifluoromethyl)benzyl)-1H-pyrazole-4-carbonyl)-2-(1- (trifluoromethyl)cyclopropane-1-carbonyl)-2,6-diazaspiro[3.4]octane-8-carboxylic acid (0.350 g, 0.64 mmol) at room temperature. After reaction became homogenous, reaction was brought to 0 °C followed by addition of DCC (0.260 g, 1.28 mmol) into the reaction solution and stirred for 2h at room temperature. Reaction mixture was diluted with water (100 mL) and was extracted by DCM (150 × 3 mL). Combined organic extracts were dried over anhydrous Na2SO4and concentrated under reduced pressure to get crude product, which was purified by silica gel column chromatography using MeOH-DCM =0.5:9.5→0.9:9.1 as gradient, to afforded (S)-N-((2S,3R)-1- oxo-3-((tetrahydro-2H-pyran-4-yl)methoxy)-1-(4-(thiazol-2-yl)piperidin-1-yl)butan-2-yl)-6-(1- (4-(trifluoromethyl)benzyl)-1H-pyrazole-4-carbonyl)-2-(1-(trifluoromethyl)cyclopropane-1- carbonyl)-2,6-diazaspiro[3.4]octane-8-carboxamide (I-79) (0.250 g, 43%) as an off white solid.1H NMR (400 MHz, DMSO-d6) δ 8.46-8.42 (m, 2H), 7.88-7.84 (m, 1H), 7.73-7.72 (d, J= 7.6 Hz, 3H,), 7.63-7.57 (m, 1H), 7.45-7.43 (d, J=8.0 Hz, 2H,), 5.48 (s, 2H), 4.94 (br. s, 1H), 4.41 (m, 1H), 4.17-3.51 (m, 11H), 3.26-3.16 (m, 5H), 2.81-2.60 (m, 1H), 2.09 (m, 2H), 1.69-1.05 (m, 16H). (There is short count of 2 protons in aliphatic region, that could be merged with either moisture or DMSO-d6signals); MS: [MH]+: 894.62.

[0288] Synthesis of 4-(1-(O-((tetrahydro-2H-pyran-4-yl)methyl)-N-((S)-6-(1-(4- (trifluoromethyl)benzyl)-1H-pyrazole-4-carbonyl)-2-(1-(trifluoromethyl)cyclopropane-1- carbonyl)-2,6-diazaspiro[3.4]octane-8-carbonyl)-L-threonyl)piperidin-4-yl)benzoic acid as (I-64)

[0289] Synthesis of N-(((4-nitrobenzyl)oxy)carbonyl)-O-((tetrahydro-2H-pyran-4-yl)methyl)-L- threonine was mentioned under (S)-N-((2S,3R)-1-oxo-3-((tetrahydro-2H-pyran-4-yl)methoxy)-1- (4-(thiazol-2-yl)piperidin-1-yl)butan-2-yl)-6-(1-(4-(trifluoromethyl)benzyl)-1H-pyrazole-4- carbonyl)-2-(1-(trifluoromethyl)cyclopropane-1-carbonyl)-2,6-diazaspiro[3.4]octane-8- carboxamide (I-79)

[0290] Synthesis of Methyl4-(1-(N-(((4-nitrobenzyl)oxy)carbonyl)-O-((tetrahydro-2H- pyran-4-yl)methyl)-L-threonyl)piperidin-4-yl)benzoate To a stirred solution of N-(((4- nitrobenzyl)oxy)carbonyl)-O-((tetrahydro-2H-pyran-4-yl)methyl)-L-threonine (1.20, 3.03 mmol) in DCM (12 mL) was added DIPEA (1.17 g, 9.09 mmol) and HATU (2.4 g, 6.31 mmol) at 00C under nitrogen. After 10 minutes of stirring at the same temperature, was added methyl 4- (piperidin-4-yl)benzoate (1.0 g, 4.54 mmol) and stirring was continued for 1h at room temperature. Reaction mixture was slowly poured into ice water (500 mL) and was extracted with DCM (200 mL × 3). Organic extracts washed with brine (400 mL), dried over anhydrous Na2SO4and concentrated under reduced pressure to get a crude product. The crude product was purified by silica gel column chromatography, using ethyl acetate-hexane = 0:1 →3:2 to afford methyl4-(1-(N-(((4-nitrobenzyl)oxy)carbonyl)-O-((tetrahydro-2H-pyran-4-yl)methyl)-L-threonyl)piperidin- 4-yl)benzoate (1.20 g, 66%) as an off-white solid. MS: [MH]+598.4.

[0291] Methyl 4-(1-(O-((tetrahydro-2H-pyran-4-yl)methyl)-L-threonyl)piperidin-4- yl)benzoate To a stirred solution of methyl4-(1-(N-(((4-nitrobenzyl)oxy)carbonyl)-O- ((tetrahydro-2H-pyran-4-yl)methyl)-L-threonyl)piperidin-4-yl)benzoate (1.0 g, 1.67 mmol) in methanol (10 mL), was added 10% Pd on activated carbon (0.500 g) at room temperature and the resulting reaction mixture was hydrogenated under balloon pressure at room temperature for 3h. Reaction mixture was filtered through celite bed, washed the bed with methanol (300 mL) and collected filtrates were concentrated under reduced pressure to get a crude product. The crude product was purified by silica gel column chromatography, using (MeOH-DCM = 0:1 →1:19) as an eluent, to afforded methyl 4-(1-(O-(tetrahydro-2H-pyran-4-yl)methyl)-L-threonyl)piperidin-4- yl)benzoate (0.700 g, 100%) as an oily liquid. MS: [MH]+419.4.

[0292] Synthesis of (S)-6-(1-(4-(Trifluoromethyl)benzyl)-1H-pyrazole-4-carbonyl)-2-(1 (trifluoromethyl)cyclopropane-1-carbonyl)-2,6-diazaspiro[3.4]octane-8-carboxylic acid was mentioned under 4-(1-(O-((2-Oxabicyclo[2.2.2]octan-4-yl)methyl)-N-((S)-6-(1-(4- (trifluoromethyl)benzyl)-1H-pyrazole-4-carbonyl)-2-(1-(trifluoromethyl)cyclopropane-1- carbonyl)-2,6-diazaspiro[3.4]octane-8-carbonyl)-L-threonyl)piperidin-4-yl)-2-hydroxybenzoic acid (I-81).

[0293] Synthesis of Methyl 4-(1-(O-((tetrahydro-2H-pyran-4-yl)methyl)-N-((S)-6-(1-(4- (trifluoromethyl)benzyl)-1H-pyrazole-4-carbonyl)-2-(1-(trifluoromethyl)cyclopropane-1- carbonyl)-2,6-diazaspiro[3.4]octane-8-carbonyl)-L-threonyl)piperidin-4-yl)benzoate a stirred solution of (S)-6-(1-(4-(trifluoromethyl)benzyl)-1H-pyrazole-4-carbonyl)-2-(1- (trifluoromethyl)cyclopropane-1-carbonyl)-2,6-diazaspiro [3.4] octane-8-carboxylic acid (0.100 g, 0.18 mmol) in DCM (1 mL) were added methyl 4-(1-(O-(tetrahydro-2H-pyran-4-yl)methyl)-L- threonyl)piperidin-4-yl)benzoate (0.076 g, 00.18 mmol) and DCC (0.076 g, 0.36 mmol) at 00C under nitrogen. The resulting reaction mixture stirred for 30 minutes at room temperature. [Another identical batch of 0.400g was performed and worked up together]. The reaction mixture was slowly poured into ice water (40 mL) and was extracted with DCM (50 mL × 3). Combined organic extracts were washed with brine (20 mL), dried over anhydrous Na2SO4 and concentrated underreduced pressure to get a crude product. Resulting crude was purified by reverse phase (C-18) silica gel column chromatography using acetonitrile-water=0:1→6:4 as gradient, to afford methyl 4-(1-(O-((tetrahydro-2H-pyran-4-yl)methyl)-N-((S)-6-(1-(4-(trifluoromethyl)benzyl)-1H- pyrazole-4-carbonyl)-2-(1-(trifluoromethyl)cyclopropane-1-carbonyl)-2,6-diazaspiro[3.4]octane- 8-carbonyl)-L-threonyl)piperidin-4-yl)benzoate (0.400 g, 58%) as an off white solid. MS: [MH]+945.5.

[0294] Synthesis of 4-(1-(O-((tetrahydro-2H-pyran-4-yl)methyl)-N-((S)-6-(1-(4- (trifluoromethyl)benzyl)-1H-pyrazole-4-carbonyl)-2-(1-(trifluoromethyl)cyclopropane-1- carbonyl)-2,6-diazaspiro[3.4]octane-8-carbonyl)-L-threonyl)piperidin-4-yl)benzoic acid (I- 64) To a stirred solution of methyl 4-(1-(O-((tetrahydro-2H-pyran-4-yl)methyl)-N-((S)-6-(1-(4- (trifluoromethyl)benzyl)-1H-pyrazole-4-carbonyl)-2-(1-(trifluoromethyl)cyclopropane-1- carbonyl)-2,6-diazaspiro[3.4]octane-8-carbonyl)-L-threonyl)piperidin-4-yl)benzoate (0.400 g, 0.42 mmol) in a mixture of THF-water (3:1; 6 mL) was added lithium hydroxide monohydrate (0.089 g, 2.11 mmol) at room temperature and the resulting reaction mixture stirred for 3h at room temperature. The reaction mixture was concentrated under reduced pressure, obtained crude was diluted with water (40 mL) and it was extracted with diethyl ether (60 mL x 2) to remove unwanted organic impurities. Aqueous part was acidified (pH ~ 2-3) with an aqueous solution of 1N HCl and was extracted with ethyl acetate (50 mL × 3). Combined organic extracts were wash with brine (100 mL), dried over anhydrous Na2SO4and concentrated under reduced pressure to get a crude product. The crude product was purified by prep-HPLC, 0.1% formic acid in water- acetonitrile / methanol / IPA as gradient, to afforded 4-(1-(O-((tetrahydro-2H-pyran-4-yl)methyl)-N- ((S)-6-(1-(4-(trifluoromethyl)benzyl)-1H-pyrazole-4-carbonyl)-2-(1- (trifluoromethyl)cyclopropane-1-carbonyl)-2,6-diazaspiro[3.4]octane-8-carbonyl)-L- threonyl)piperidin-4-yl)benzoic acid (0.350 g, 89%) as an off-white solid. MS: [MH]+931.5. Note: Though Applicant started with chiral intermediates, they observed racemization in the final compound as observed by Chiral HPLC. So they further separated each enantiomer by chiral SFC.

[0295] 4-(1-(O-((tetrahydro-2H-pyran-4-yl)methyl)-N-((S)-6-(1-(4-(trifluoromethyl)benzyl)- 1H-pyrazole-4-carbonyl)-2-(1-(trifluoromethyl)cyclopropane-1-carbonyl)-2,6- diazaspiro[3.4]octane-8-carbonyl)-L-threonyl)piperidin-4-yl)benzoic acid (I-61 (A)) (0.035g, 8%) as a white solid.1H-NMR (400 MHz, DMSO-d6) δ 12.76 (br, 1H), 8.48-8.42 (m, 2H), 7.90-7.84 (m, 3H), 7.73-7.71 (d, J=7.6 Hz, 2H), 7.44-7.32 (m, 4H), 5.48 (s, 2H), 4.94 (brs, 1H), 4.54- 3.34 (m, 12H), 3.29-2.67 (m, 7H), 1.97-1.54 (m, 10H), 1.16-1.04 (m, 7H), 0.86-0.82 (m, 1H). MS: [MH]+931.6.

[0296] 4-(1-(O-((tetrahydro-2H-pyran-4-yl)methyl)-N-((S)-6-(1-(4-(trifluoromethyl)benzyl)- 1H-pyrazole-4-carbonyl)-2-(1-(trifluoromethyl)cyclopropane-1-carbonyl)-2,6- diazaspiro[3.4]octane-8-carbonyl)-L-threonyl)piperidin-4-yl)benzoic acid (I-64 (B)) (0.030g, 8%) as a white solid.1H-NMR (400 MHz, DMSO-d6) δ 12.81 (br, 1H), 8.65-8.50 (m, 1H), 8.44- 8.41 (d, J=11.2 Hz, 1H), 7.87-7.83 (m, 3H), 7.73-7.71 (d, J=7.6 Hz, 2H), 7.44-7.42 (d, J=7.6 Hz, 2H), 7.33 (brs, 2H), 5.48 (s, 2H), 4.86 (brs, 1H), 4.54 (brs, 1H), 4.20-3.47 (m, 11H), 3.20-3.10 (m, 3H), 2.90 (br, 1H), 2.67-2.57 (m, 2H), 1.97-1.81 (m, 3H), 1.72-1.51 (m, 5H), 1.41-1.11 (10H), 0.92-0.86 (m, 1H). MS: [MH]+931.6.

[0297] Synthesis of tert-Butyl 4-(4-(methoxycarbonyl)phenyl)-3,6-dihydropyridine-1(2H)- carboxylate To a stirred solution of methyl 4-bromobenzoate (3.0 g, 13.95 mmol) in DMF (30 mL) were added tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine- 1(2H)-carboxylate (4.31 g, 13.95 mmol) and K2CO3(5.77 g, 41.85 mmol) sequentially at room temperature. The reaction mixture was degassed (purging with nitrogen) for 20 min followed by the addition of Pd(PPh3)4(0.805 g, 0.697 mmol) and the reaction mixture was heated at 900C for 4h. After cooling to room temperature, reaction was diluted with water (200 mL) and was extracted with diethyl ether (100 mL × 3). Collected organic extracts were washed with brine (200 mL), dried over anhydrous Na2SO4and concentrated under reduce pressure. The crude product was purified by silica gel column chromatography, using ethyl acetate-hexane = 0:1→0.7:9.3 as gradient, to afford tert-Butyl 4-(4-(methoxycarbonyl)phenyl)-3,6-dihydropyridine-1(2H)- carboxylate (3.20 g, 69%) as a colorless oil. MS: [MH]+318.1.

[0298] Synthesis of tert-Butyl 4-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylate To a stirred solution of tert-Butyl 4-(4-(methoxycarbonyl)phenyl)-3,6-dihydropyridine-1(2H)- carboxylate (3.2 g, 10.09 mmol) in a methanol (28 mL) was added 10% Pd in activated carbon (2.0 g) at room temperature under nitrogen and the resulting mixture was hydrogenated under balloon pressure at the same temperature for 2h. Reaction mixture was filter through a celite bed, washed the bed with methanol (100 mL) and collected filtrates were concentrated under reduced pressure to afford tert-Butyl 4-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylate (2.70 g, 86%) as a colorless oil. MS: [MH]+220.1.

[0299] Synthesis of Methyl 4-(piperidin-4-yl)benzoate To a stirred solution of tert-Butyl 4-(4- (methoxycarbonyl)phenyl)piperidine-1-carboxylate (2.70 g, 8.46 mmol) in DCM (25.0 mL) was added 4M HCl in dioxane (10.0 mL) at 00C and stirred the solution at room temperature for 1h. Reaction mixture was concentrated under reduced pressure to obtained crude product, which was purified by trituration using n-pentane, to afford methyl 4-(piperidin-4-yl)benzoate hydrochloride (2.20 g, quantitative) as an off-white solid. MS: [MH]+169.1.

[0300] Synthesis of (S)-6-(5-hydroxypyrazine-2-carbonyl)-N-((2S,3R)-1-oxo-3-((tetrahydro- 2H-pyran-4-yl)methoxy)-1-(4-(trifluoromethyl)piperidin-1-yl)butan-2-yl)-2-(1- (trifluoromethyl)cyclopropane-1-carbonyl)-2,6-diazaspiro[3.4]octane-8-carboxamide (I-78)

[0301] Synthesis of 4-Nitrobenzyl ((2S,3R)-1-oxo-3-((tetrahydro-2H-pyran-4-yl)methoxy)-1- (4-(trifluoromethyl)piperidin-1-yl)butan-2-yl)carbamate To a stirred solution of N-(((4-nitrobenzyl)oxy)carbonyl)-O-((tetrahydro-2H-pyran-4-yl)methyl)-L-threonine 1.30 g, 3.282 mmol) in DCM (10 mL) was added DIPEA (0.820 g, 6.56 mmol) and HATU (1.87 g, 4.92 mmol) at 00C under nitrogen. After 10 min of stirring at the same temperature, was added 4- (trifluoromethyl)piperidine (0.48 g, 3.282 mmol) and stirring was continued for 1h at room temperature. Reaction mixture was slowly poured into ice water (50 mL) and was extracted with ethyl acetate (50 mL × 3). Combined organic extracts were washed with brine (20 mL), dried over anhydrous Na2SO4and concentrated under reduced pressure to get a crude product. The crude product was purified by column chromatography on silica gel using MeOH-DCM = 0:1 →1:19 to afford 4-nitrobenzyl ((2S,3R)-1-oxo-3-((tetrahydro-2H-pyran-4-yl)methoxy)-1-(4- (trifluoromethyl)piperidin-1-yl)butan-2-yl)carbamate (1.0 g, 57%) as a colourless gummy oil. MS: [MH]+532.5.

[0302] Synthesis of (2S,3R)-2-amino-3-((tetrahydro-2H-pyran-4-yl)methoxy)-1-(4- (trifluoromethyl)piperidin-1-yl)butan-1-one 10% Pd in activated carbon (0.500 g) was added carefully to a stirred solution of 4-nitrobenzyl ((2S,3R)-1-oxo-3-((tetrahydro-2H-pyran-4- yl)methoxy)-1-(4-(trifluoromethyl)piperidin-1-yl)butan-2-yl)carbamate (1.0 g, 1.88 mmol) in a methanol (10 mL) at room temperature under nitrogen and the resulting mixture was hydrogenated under balloon pressure at the same temperature for 2h. The reaction mixture was filtered through a celite bed, washed the bed with methanol (30 mL x 2) and collected filtrates were concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel using MeOH:DCM = 0:1 →1:19 as eluent, to afford (2S,3R)-2-amino-3-((tetrahydro-2H-pyran-4- yl)methoxy)-1-(4-(trifluoromethyl)piperidin-1-yl)butan-1-one (0.420 g, 67%) as a colourless gummy. MS: [MH]+353.5.

[0303] Synthesis of (S)-6-(5-hydroxypyrazine-2-carbonyl)-N-((2S,3R)-1-oxo-3-((tetrahydro- 2H-pyran-4-yl)methoxy)-1-(4-(trifluoromethyl)piperidin-1-yl)butan-2-yl)-2-(1- (trifluoromethyl)cyclopropane-1-carbonyl)-2,6-diazaspiro[3.4]octane-8-carboxamide To a stirred solution of (S)-6-(5-hydroxypyrazine-2-carbonyl)-2-(1-(trifluoromethyl)cyclopropane-1- carbonyl)-2,6-diazaspiro[3.4]octane-8-carboxylic acid (0.300 g, 0.72 mmol) in DCM (5 mL) were added (2S,3R)-2-amino-3-((tetrahydro-2H-pyran-4-yl)methoxy)-1-(4-(trifluoromethyl)piperidin- 1-yl)butan-1-one (0.382 g, 1.086 mmol) and DCC (0.298 g, 1.448 mmol) sequentially at 00C under nitrogen and the resulting reaction mixture was stirred for 2h at room temperature. Reactionmixture was slowly poured into ice water (20 mL) and was extracted with DCM (30 mL × 3). Combined organic extracts were washed with brine (20 mL), dried over anhydrous Na2SO4and concentrated under reduced pressure to get a crude product. The crude product was purified by Prep HPLC, 0.1% formic acid in water-acetonitrile as a gradient, to afford (S)-6-(5- hydroxypyrazine-2-carbonyl)-N-((2S,3R)-1-oxo-3-((tetrahydro-2H-pyran-4-yl)methoxy)-1-(4- (trifluoromethyl)piperidin-1-yl)butan-2-yl)-2-(1-(trifluoromethyl)cyclopropane-1-carbonyl)-2,6- diazaspiro[3.4]octane-8-carboxamide (0.080 g, 15%) as a white solid.1H-NMR (400 MHz, DMSO-d6) δ 12.83 (br, 1H), 8.50-8.43 (m, 1H), 7.93-7.89 (m, 2H), 4.88 (br, 1H), 4.51-4.46 (m, 2H), 4.25-3.97 (m, 5H), 3.82-3.80 (d, J=8.8 Hz, 4H), 3.60 (br, 3H), 3.34-3.07 (m, 5H), 2.60-2.55 (m, 3H), 1.90-1.52 (m, 5H), 1.23-1.03 (m, 10H). MS: [MH]+749.4.

[0304] Synthesis of (S)-6-(3-hydroxypyrazine-2-carbonyl)-N-((2S,3R)-1-oxo-1-(6- azaspiro[2.5]octan-6-yl)-3-((tetrahydro-2H-pyran-4-yl)methoxy)butan-2-yl)-2-(1- (trifluoromethyl)cyclopropane-1-carbonyl)-2,6-diazaspiro[3.4]octane-8-carboxamide (I-77)

[0305] Synthesis of ((R)-3-((S)-6-(3-hydroxypyrazine-2-carbonyl)-2-(1- (trifluoromethyl)cyclopropane-1-carbonyl)-2,6-diazaspiro[3.4]octane-8-carbonyl)-4- phenyloxazolidin-2-one To a stirred solution of 3-hydroxypyrazine-2-carboxylic acid (1.0 g, 7.14 mmol) in DCM (40 mL) were added (R)-4-phenyl-3-((S)-2-(1-(trifluoromethyl)cyclopropane-1- carbonyl)-2,6-diazaspiro[3.4]octane-8-carbonyl)oxazolidin-2-one (2.5 g, 5.71 mmol) and DCC (2.9 g, 14.28 mmol) sequentially at room temperature under nitrogen and stirring was continued for 2h at the same temperature. Reaction mixture was slowly poured into ice water (50 mL) andwas extracted with ethyl acetate (100 mL × 2). Combined organic extracts were washed with brine (150 mL), dried over anhydrous Na2SO4and concentrated under reduced pressure to get a crude product, which was purified by column chromatography on silica gel, using MeOH-DCM = 0:1 →1:19 as eluent, to afford (R)-3-((S)-6-(3-hydroxypyrazine-2-carbonyl)-2-(1- (trifluoromethyl)cyclopropane-1-carbonyl)-2,6-diazaspiro[3.4]octane-8-carbonyl)-4- phenyloxazolidin-2-one (3.7 g, 93 %) as a yellow solid. MS: [MH]+560.3.

[0306] Synthesis of (S)-6-(3-hydroxypyrazine-2-carbonyl)-2-(1- (trifluoromethyl)cyclopropane-1-carbonyl)-2,6-diazaspiro[3.4]octane-8-carboxylic acid To a stirred solution of (R)-3-((S)-6-(3-hydroxypyrazine-2-carbonyl)-2-(1- (trifluoromethyl)cyclopropane-1-carbonyl)-2,6-diazaspiro[3.4]octane-8-carbonyl)-4- phenyloxazolidin-2-one (1.0 g, 1.78 mmol) in a mixture of THF-water (5:1; 6 mL) was added H2O2(30% in water; 8.0 mL) at 0° C and the resulting mixture was stirred at room temperature for 2h. After 2h of stirring, reaction was cooled to 0° C and was added LiOH:H2O (0.142 g, 3.39 mmol) and stirred at room temperature for an additional 1h. Reaction was diluted with water (10 mL) and was washed with ethyl acetate (30 mL) to get rid of unwanted organic impurities. Separated aqueous layer was acidified (pH ~ 2-3) with an aqueous solution of 1N HCl and was extracted with 20 % IPA-CHCl3solution (100 mL × 3). Combined organic extracts was dried over anhydrous Na2SO4and concentrated under reduced pressure to afford (S)-6-(3-hydroxypyrazine- 2-carbonyl)-2-(1-(trifluoromethyl)cyclopropane-1-carbonyl)-2,6-diazaspiro[3.4]octane-8- carboxylic acid (0.360 g, 48%) as an off white solid. MS: [MH]+415.2.

[0307] Synthesis of 4-Nitrobenzyl ((2S,3R)-1-oxo-1-(6-azaspiro[2.5]octan-6-yl)-3- ((tetrahydro-2H-pyran-4-yl)methoxy)butan-2-yl)carbamate To a stirred solution of N-(((4- nitrobenzyl)oxy)carbonyl)-O-((tetrahydro-2H-pyran-4-yl)methyl)-L-threonine (1.0 g, 2.52 mmol) in DCM (10 mL) were added DIPEA (0.97 g, 7.57 mmol) and HATU (2.39 g, 6.31 mmol) at 00C under nitrogen. After 10 min of stirring at the same temperature, was added 6-azaspiro[2.5]octane (0.45 g, 3.03 mmol) and stirring was continued for 2h at room temperature. Reaction mixture was slowly poured into ice water (50 mL) and was extracted with ethyl acetate (50 mL × 3). Combined organic extracts were washed with brine (20 mL), dried over anhydrous Na2SO4and concentrated under reduced pressure to get a crude product. The crude product was purified by column chromatography on silica gel using MeOH-DCM = 0:1 →1:19 as an eluent, to afford 4-nitrobenzyl((2S,3R)-1-oxo-1-(6-azaspiro[2.5]octan-6-yl)-3-((tetrahydro-2H-pyran-4-yl)methoxy)butan-2- yl)carbamate (0.800 g, 66%) as a colourless gummy oil. MS: [MH]+490.3.

[0308] Synthesis of (2S,3R)-2-amino-1-(6-azaspiro[2.5]octan-6-yl)-3-((tetrahydro-2H-pyran- 4-yl)methoxy)butan-1-one 10% Pd on activated carbon (0.300 g) was added carefully to a stirred solution of 4-nitrobenzyl ((2S,3R)-1-oxo-1-(6-azaspiro[2.5]octan-6-yl)-3-((tetrahydro-2H-pyran- 4-yl)methoxy)butan-2-yl)carbamate (0.700 g, 1.43 mmol) in a methanol (8 mL) at room temperature under nitrogen and the resulting mixture was hydrogenated under balloon pressure for 2h at the same temperature. Reaction mixture was filtered through a celite bed, washed the bed with methanol (30 mL x 2) and collected filtrates were concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel using MeOH: DCM = 0:1 →1:19 to afford (2S,3R)-2-amino-1-(6-azaspiro[2.5]octan-6-yl)-3-((tetrahydro-2H-pyran-4- yl)methoxy)butan-1-one (0.450 g, 88%) as a colourless gummy oil. MS: [MH]+311.3.

[0309] Synthesis of (S)-6-(3-hydroxypyrazine-2-carbonyl)-N-((2S,3R)-1-oxo-1-(6- azaspiro[2.5]octan-6-yl)-3-((tetrahydro-2H-pyran-4-yl)methoxy)butan-2-yl)-2-(1- (trifluoromethyl)cyclopropane-1-carbonyl)-2,6-diazaspiro[3.4]octane-8-carboxamide (I-77) To a stirred solution of (S)-6-(3-hydroxypyrazine-2-carbonyl)-2-(1- (trifluoromethyl)cyclopropane-1-carbonyl)-2,6-diazaspiro[3.4]octane-8-carboxylic acid (0.350 g, 0.84 mmol) in DCM (6 mL) were added (2S,3R)-2-amino-1-(6-azaspiro[2.5]octan-6-yl)-3- ((tetrahydro-2H-pyran-4-yl)methoxy)butan-1-one (0.392 g, 1.26 mmol) and DCC (0.348 g, 1.69 mmol) at 00C under nitrogen and the resulting reaction mixture was stirred for 2h at room temperature. The reaction mixture was slowly poured into ice water (20 mL) and was extracted with DCM (30 mL × 3). Combined organic extracts were washed with brine (20 mL), dried over anhydrous Na2SO4and concentrated under reduced pressure to get a crude product. The crude product was purified by Prep HPLC, using 0.1% formic acid in water-acetonitrile as a gradient, to afford (S)-6-(3-hydroxypyrazine-2-carbonyl)-N-((2S,3R)-1-oxo-1-(6-azaspiro[2.5]octan-6-yl)-3- ((tetrahydro-2H-pyran-4-yl)methoxy)butan-2-yl)-2-(1-(trifluoromethyl)cyclopropane-1- carbonyl)-2,6-diazaspiro[3.4]octane-8-carboxamidee (I-77) (0.070 g, 11%) as a white solid.1H- NMR (400 MHz, DMSO-d6) δ 12.69 (brs, 1H), 8.48-8.38 (m, 1H), 7.57 (brs, 1H), 7.38 (brs, 1H), 4.89 (br. s, 1H), 4.40-4.02 (m, 3H), 3.82-3.79 (d, J=8.8 Hz, 3H), 3.63-3.46 (m, 9H), 3.27-3.18 (m,4H), 2.60-2.45 (m, 3H, merged in DMSO-d6), 1.68 (brs, 1H), 1.55-1.52 (d, J=13.2 Hz, 2H), 1.32- 1.02 (m, 12H), 0.35-0.33 (m, 3H). MS: [MH]+707.4. MS: [MH]+707.4.

[0310] Synthesis of (S)-N-((2S,3R)-1-oxo-1-(2-oxa-7-azaspiro[3.5]nonan-7-yl)-3- ((tetrahydro-2H-pyran-4-yl)methoxy)butan-2-yl)-6-(1-(4-(trifluoromethyl)benzyl)-1H- pyrazole-4-carbonyl)-2-(1-(trifluoromethyl)cyclopropane-1-carbonyl)-2,6- diazaspiro[3.4]octane-8-carboxamide (I-67)

[0311] Synthesis of 1-(tert-Butyl) 4,4-diethyl piperidine-1,4,4-tricarboxylate To a stirred solution of 1-(tert-butyl) 4-ethyl piperidine-1,4-dicarboxylate (5.0 g, 19.40 mmol) in dry THF (10 mL) was added LDA (11.6 mL, 23.2 mmol) drop-wise at -78 °C under nitrogen over period of 30 min. After stirring for 1h at the same temperature, was added ethyl chloroformate (2.10 g, 19.4 mmol) into the reaction mixture and stirring was continued for an additional 2h at -780C. Reaction mixture was slowly brought to room temperature, quenched with an aqueous solution of saturated ammonium chloride (100 mL) and was extracted with ethyl acetate (100 mL × 3). Combined organic extracts were dried over anhydrous Na2SO4and concentrated under reduce pressure to give 1-(tert-butyl) 4,4-diethyl piperidine-1,4,4-tricarboxylate (7.0 g, quant.; crude) as a yellow oil. MS: [MH-100]+230.20.

[0312] Synthesis of tert-Butyl 4,4-bis(hydroxymethyl)piperidine-1-carboxylate To a stirred solution of 1-(tert-butyl) 4,4-diethyl piperidine-1,4,4-tricarboxylate (7.0 g, 21.2 mmol) in a dry THF (30 mL) was added lithium borohydride (88 mL, 170.00 mmol) drop-wise at -780C overperiod of 30 min. The reaction mixture was heated at 600C for 48h. Reaction mixture was cooled to room temperature, diluted with water (100 mL) and was extracted with ethyl acetate (100 mL × 3). Combined organic extracts were dried over anhydrous Na2SO4and concentrated under reduce pressure to obtained crude product. The crude product was purified by reverse-phase column chromatography, using water-acetonitrile = 0:10→8:2 as a gradient, to afford tert-butyl 4,4- bis(hydroxymethyl)piperidine-1-carboxylate (3.2 g, 61%) as a white solid. MS: [MH-100]+146.10.

[0313] Synthesis of tert-Butyl 4-(hydroxymethyl)-4-((tosyloxy)methyl) piperidine-1- carboxylate To a stirred solution of tert-butyl 4,4-bis(hydroxymethyl)piperidine-1-carboxylate (2.20 g, 8.90 mmol) in pyridine (20 mL) was added DMAP (0.109g, 0.89 mmol) at 00C under nitrogen. After stirring for 30 minutes at same temperature, was added tosyl-chloride (1.7g, 8.90 mmol) and stirring was continued at room temperature for 16h. Reaction mixture was diluted with water (100 mL) and was extracted with ethyl acetate (100 mL × 3). Combined organic extracts were dried over anhydrous Na2SO4and concentrated under reduce pressure to afforded tert-butyl 4-(hydroxymethyl)-4-((tosyloxy)methyl) piperidine-1-carboxylate (2.50 g, 70%; crude) as a yellow oil MS: [MH-100]+300.20.

[0314] Synthesis of tert-Butyl 2-oxa-7-azaspiro [3.5] nonane-7-carboxylate To a stirred solution of tert-butyl 4-(hydroxymethyl)-4-((tosyloxy)methyl) piperidine-1-carboxylate (2.50 g, 6.26 mmol) in DMF (20 mL) was added NaH (60% dispersion on oil; 0.751 g, 18.70 mmol) portion wise at 00C under nitrogen and the reaction mixture was stirred at room temperature for 16h. Reaction mixture was diluted with cooled water (100 mL) and was extracted with ethyl acetate (100 mL × 3). Combined organic extracts were dried over anhydrous Na2SO4and concentrated under reduce pressure to obtained crude product, which was purified by flash column chromatography, using ethyl acetate-hexane: = 0:1→3:2 as a gradient, to afford tert-butyl 2-oxa- 7-azaspiro [3.5] nonane-7-carboxylate (1.0 g, 70%) as a white solid. MS: [MH-56]+172.10.

[0315] Synthesis of 2-Oxa-7-azaspiro [3.5] nonane To a stirred solution of tert-butyl 2-oxa-7- azaspiro [3.5] nonane-7-carboxylate (1.0 g, 4.40 mmol) in DCM (5 mL) was added TFA (1.5 mL) at 00C and the resulting reaction mixture was stirred at room temperature for 1h. The reaction mixture was concentrated under reduced pressure and the obtained crude product was purified bytrituration with DCM-diethyl ether, to afforded 2-oxa-7-azaspiro [3.5] nonane (0.900 g, quant; crude) as a brown sticky solid. MS: [MH]+128.10.

[0316] Synthesis of N-(((4-nitrobenzyl)oxy)carbonyl)-O-((tetrahydro-2H-pyran-4- yl)methyl)-L-threonine mentioned under (S)-N-((2S,3R)-1-oxo-3-((tetrahydro-2H-pyran-4- yl)methoxy)-1-(4-(thiazol-2-yl)piperidin-1-yl)butan-2-yl)-6-(1-(4-(trifluoromethyl)benzyl)- 1H-pyrazole-4-carbonyl)-2-(1-(trifluoromethyl)cyclopropane-1-carbonyl)-2,6- diazaspiro[3.4]octane-8-carboxamide, intermediate:

[0317] Synthesis of 4-Nitrobenzyl ((2S,3R)-1-oxo-1-(2-oxa-7-azaspiro[3.5]nonan-7-yl)-3- ((tetrahydro-2H-pyran-4-yl)methoxy)butan-2-yl)carbamate To a stirred solution of N-(((4- nitrobenzyl)oxy)carbonyl)-O-((tetrahydro-2H-pyran-4-yl)methyl)-L-threonine (0.500 g, 1.26 mmol) in DCM (4 mL) were added DIPEA (0.488 g, 3.78 mmol) and HATU (0.718 g, 1.89 mmol) at 00C under nitrogen. After 10 min of stirring at the same temperature, was added 2-oxa-7- azaspiro[3.5]nonane (0.192 g, 1.51 mmol) and stirring was continued for 1.5h at room temperature. [Another identical batch of 0.500g was performed and worked up together]. Reaction mixture slowly poured in to water (100.0 mL) and was extracted with ethyl acetate (100 mL × 3). Combined organic extracts were, dried over anhydrous Na2SO4and concentrated under reduced pressure to get a crude product. The crude product was purified by silica gel column chromatography, using MeOH: DCM = 0:1 →1:4 as an eluent, to afforded 4-nitrobenzyl ((2S,3R)-1-oxo-1-(2-oxa-7- azaspiro [3.5] nonan-7-yl)-3-((tetrahydro-2H-pyran-4-yl)methoxy)butan-2-yl)carbamate (0.900 g, 70%) as a yellow sticky solid. MS: [MH]+506.3.

[0318] Synthesis of (2S,3R)-2-amino-1-(2-oxa-7-azaspiro[3.5]nonan-7-yl)-3-((tetrahydro- 2H-pyran-4-yl)methoxy)butan-1-one 10% Pd on activated carbon (0.450 g) was added carefully to a stirred solution of 4-nitrobenzyl ((2S,3R)-1-oxo-1-(2-oxa-7-azaspiro [3.5] nonan-7-yl)-3- ((tetrahydro-2H-pyran-4-yl)methoxy)butan-2-yl)carbamate (0.900 g, 1.78 mmol) in methanol (8 mL) at room temperature under nitrogen and the resulting mixture was hydrogenated under balloonpressure at the same temperature for 3h. Reaction mixture was filtered through a celite bed, washed the bed with methanol (100 mL) and collected filtrates were concentrated under reduced pressure. The crude product was purified by silica gel column chromatography, using MeOH: DCM = 0:1 →1:19 as an eluent, to afforded (2S,3R)-2-amino-1-(2-oxa-7-azaspiro[3.5]nonan-7-yl)-3- ((tetrahydro-2H-pyran-4-yl)methoxy)butan-1-one (0.500 g, 86%) as a brown sticky mass. MS: [MH]+327.3.

[0319] Synthetic procedure of (S)-6-(1-(4-(Trifluoromethyl)benzyl)-1H-pyrazole-4-carbonyl)-2- (1 (trifluoromethyl)cyclopropane-1-carbonyl)-2,6-diazaspiro[3.4]octane-8-carboxylic acid mentioned under target 4-(1-(O-((2-Oxabicyclo[2.2.2]octan-4-yl)methyl)-N-((S)-6-(1-(4- (trifluoromethyl)benzyl)-1H-pyrazole-4-carbonyl)-2-(1-(trifluoromethyl)cyclopropane-1- carbonyl)-2,6-diazaspiro[3.4]octane-8-carbonyl)-L-threonyl)piperidin-4-yl)-2-hydroxybenzoic acid (I-81)

[0320] Synthesis of (S)-N-((2S,3R)-1-oxo-1-(2-oxa-7-azaspiro [3.5] nonan-7-yl)-3- ((tetrahydro-2H-pyran-4-yl) methoxy) butan-2-yl)-6-(1-(4-(trifluoromethyl) benzyl)-1H- pyrazole-4-carbonyl)-2-(1-(trifluoromethyl)cyclopropane-1-carbonyl)-2,6- diazaspiro[3.4]octane-8-carboxamide (I-67): To a stirred suspension of (S)-6-(1-(4- (trifluoromethyl)benzyl)-1H-pyrazole-4-carbonyl)-2-(1-(trifluoromethyl)cyclopropane-1- carbonyl)-2,6-diazaspiro[3.4]octane-8-carboxylic acid (0.300 g, 0.55 mmol) and (2S,3R)-2- amino-1-(2-oxa-7-azaspiro[3.5]nonan-7-yl)-3-((tetrahydro-2H-pyran-4-yl)methoxy)butan-1-one (0.361 g, 1.10 mmol) in DCM (3 mL) were added triethylamine (0.166 g, 1.65 mmol) and T3P (0.350 g, 1.10 mmol) at room temperature under nitrogen and stirred for 4h at the same temperature. Reaction mixture was diluted with water (100 mL) and was extracted with dichloromethane (100 x 2 mL). Combined organic extracts were dried over anhydrous Na2SO4and concentrated under reduce pressure. The crude product was purified by revers-phase column chromatography using acetonitrile: water- = 0:1→4:6 as gradient, to afforded (S)-N-((2S,3R)-1- oxo-1-(2-oxa-7-azaspiro [3.5] nonan-7-yl)-3-((tetrahydro-2H-pyran-4-yl) methoxy) butan-2-yl)- 6-(1-(4-(trifluoromethyl) benzyl)-1H-pyrazole-4-carbonyl)-2-(1-(trifluoromethyl)cyclopropane- 1-carbonyl)-2,6-diazaspiro[3.4]octane-8-carboxamide (0.130 g, 28%) as a white solid.1H-NMR (400 MHz, DMSO-d6) δ 8.46-8.40 (m, 2H), 7.87-7.83 (d, J=16.8 Hz, 1H), 7.73-7.71 (d, J=8.0 Hz, 2H), 7.44-7.43 (d, J=7.6 Hz, 2H), 5.48-5.47 (d, J=6.0 Hz, 2H), 4.86 (br. s, 1H), 4.31-4.12 (m, 6H),4.12-3.90 (m, 2H), 3.90-3.70 (m, 4H), 3.70-3.50 (m, 3H), 3.50-3.36 (m, 3H), 3.24-3.19 (m, 3H), 2.57-2.54 (m, 2H; merged in DMSO-d6), 1.82-1.64 (m, 4H), 1.54-1.47 (m, 2H), 1.37-1.04 (m, 7H), 1.03-0.98 (d, J=6.0 Hz, 2H). MS: [MH]+853.60.

[0321] Synthesis of (8S)-N-((2S,3R)-3-((2-oxabicyclo[2.2.2]octan-4-yl)methoxy)-1-oxo-1-(4- (thiazol-2-yl)piperidin-1-yl)butan-2-yl)-2-((tetrahydrofuran-2-yl)methyl)-6-(thiazole-5- carbonyl)-2,6-diazaspiro[3.4]octane-8-carboxamide (I-44)

[0322] Step 1: tert-butyl (S)-8-(((2S,3R)-3-((2-oxabicyclo[2.2.2]octan-4-yl)methoxy)-1-oxo-1- (4-(thiazol-2-yl)piperidin-1-yl)butan-2-yl)carbamoyl)-6-(thiazole-5-carbonyl)-2,6- diazaspiro[3.4]octane-2-carboxylate: To a solution of (S)-2-(tert-butoxycarbonyl)-6-(thiazole- 5-carbonyl)-2,6-diazaspiro[3.4]octane-8-carboxylic acid (206 mg, 0.56 mmol) in DCM (4 mL) was added HATU (213 mg, 0.56 mmol) and DIPEA (217 mg, 1.68 mmol) and the mixture stirred at room temperature for 30 min. (2S,3R)-3-((2-oxabicyclo[2.2.2]octan-4-yl)methoxy)-2-amino-1- (4-(thiazol-2-yl)piperidin-1-yl)butan-1-one (220 mg, 0.56 mmol) was added and the reaction stirred a further 2 h. The reaction was diluted with water (30 mL) and extracted with DCM (50 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue obtained was purified by RP-column to afford tert-butyl (S)-8- (((2S,3R)-3-((2-oxabicyclo[2.2.2]octan-4-yl)methoxy)-1-oxo-1-(4-(thiazol-2-yl)piperidin-1- yl)butan-2-yl)carbamoyl)-6-(thiazole-5-carbonyl)-2,6-diazaspiro[3.4]octane-2-carboxylate (170 mg, 45%) as a white solid. LCMS m / z =743.2 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 9.31 – 9.20 (m, 1H), 8.36 (dd, J = 20.2, 12.3 Hz, 2H), 7.76 – 7.08 (m, 3H), 4.96 – 4.12 (m, 2H), 4.11 – 3.70 (m, 10H), 3.67 – 3.54 (m, 3H), 3.51 – 3.34 (m, 2H), 3.27 – 2.70 (m, 2H), 2.25 (s, 1H), 2.14 – 1.78 (m, 3H), 1.73 – 1.46 (m, 4H), 1.37 (d, J = 5.4 Hz, 9H), 1.34 (s, 3H), 1.24 (s, 1H), 1.17 (t, J = 7.1 Hz, 1H), 1.04 (s, 2H).

[0323] Step 2: (S)-N-((2S,3R)-3-((2-oxabicyclo[2.2.2]octan-4-yl)methoxy)-1-oxo-1-(4- (thiazol-2-yl)piperidin-1-yl)butan-2-yl)-6-(thiazole-5-carbonyl)-2,6-diazaspiro[3.4]octane-8-carboxamide: To a solution of tert-butyl (S)-8-(((2S,3R)-3-((2-oxabicyclo[2.2.2]octan-4- yl)methoxy)-1-oxo-1-(4-(thiazol-2-yl)piperidin-1-yl)butan-2-yl)carbamoyl)-6-(thiazole-5- carbonyl)-2,6-diazaspiro[3.4]octane-2-carboxylate (85 mg, 0.11 mmol) in DCM (2 mL) was added TFA (1 mL) and the reaction stirred at room temperature for 2 h. The solvent was removed under vacuum to afford (S)-N-((2S,3R)-3-((2-oxabicyclo[2.2.2]octan-4-yl)methoxy)-1-oxo-1-(4- (thiazol-2-yl)piperidin-1-yl)butan-2-yl)-6-(thiazole-5-carbonyl)-2,6-diazaspiro[3.4]octane-8- carboxamide (50 mg, 100%) which was used directly in the next step. LCMS m / z = 643.2 [M+H]+.

[0324] Step 3: (8S)-N-((2S,3R)-3-((2-oxabicyclo[2.2.2]octan-4-yl)methoxy)-1-oxo-1-(4- (thiazol-2-yl)piperidin-1-yl)butan-2-yl)-2-((tetrahydrofuran-2-yl)methyl)-6-(thiazole-5- carbonyl)-2,6-diazaspiro[3.4]octane-8-carboxamide (I-44): To a solution of (S)-N-((2S,3R)-3- ((2-oxabicyclo[2.2.2]octan-4-yl)methoxy)-1-oxo-1-(4-(thiazol-2-yl)piperidin-1-yl)butan-2-yl)-6- (thiazole-5-carbonyl)-2,6-diazaspiro[3.4]octane-8-carboxamide (50 mg, 0.10 mmol) in MeCN (2 mL) was added Na2CO3(27 mg, 0.30 mmol) and 2-(bromomethyl)tetrahydrofuran (18 mg, 0.10 mmol). The mixture was heated at 100 °C in a microwave reactor for 2 h. The mixture was filtered through celite and the filtrate concentrated. The residue obtained was purified by prep-HPLC to afford (8S)-N-((2S,3R)-3-((2-oxabicyclo[2.2.2]octan-4-yl)methoxy)-1-oxo-1-(4-(thiazol-2- yl)piperidin-1-yl)butan-2-yl)-2-((tetrahydrofuran-2-yl)methyl)-6-(thiazole-5-carbonyl)-2,6- diazaspiro[3.4]octane-8-carboxamide (12.4 mg, 19%) as a white solid. LCMS m / z = 727.3 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 9.26 (s, 1H), 8.41 – 8.25 (m, 2H), 8.14 (s, 1H), 7.77 – 7.54 (m, 2H), 4.87 (s, 1H), 4.41 (s, 1H), 4.26 – 3.68 (m, 8H), 3.67 – 3.59 (m, 4H), 3.58 – 3.53 (m, 2H), 3.25 – 3.12 (m, 3H), 3.06 – 3.01 (m, 1H), 2.86 – 2.72 (m, 2H), 2.18 – 1.70 (m, 8H), 1.64 – 1.33 (m, 10H), 1.07 (s, 3H). Building blocks:

[0325] (2S,3R)-3-((2-oxabicyclo[2.2.2]octan-4-yl)methoxy)-2-amino-1-(4-(thiazol-2- yl)piperidin-1-yl)butan-1-one

[0326] Step 1: O-((2-oxabicyclo[2.2.2]octan-4-yl)methyl)-N-(((4-nitrobenzyl)oxy)carbonyl)- L-threonine: To a solution of methyl O-((2-oxabicyclo[2.2.2]octan-4-yl)methyl)-N-(((4- nitrobenzyl)oxy)carbonyl)-L-threoninate (100 mg, 0.23 mmol) in a mixture of THF, water and MeOH (2.0 mL / 0.5 mL / 0.5 mL) was added LiOH (24 mg, 0.57 mmol) and the reaction stirred at room temperature for 2 h. The reaction was diluted with water (10 mL) and extracted with ether (30 mL). The aqueous layer was collected and acidified to pH ~ 2 with 1M HCl then extracted with EtOAc (40 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to afford O-((2-oxabicyclo[2.2.2]octan-4-yl)methyl)-N-(((4- nitrobenzyl)oxy)carbonyl)-L-threonine (95 mg, 98%) as a white solid. LCMS m / z = 423.1 [M+H]+.

[0327] Step 2: 4-nitrobenzyl ((2S,3R)-3-((2-oxabicyclo[2.2.2]octan-4-yl)methoxy)-1-oxo-1-(4- (thiazol-2-yl)piperidin-1-yl)butan-2-yl)carbamate: To a solution of O-((2- oxabicyclo[2.2.2]octan-4-yl)methyl)-N-(((4-nitrobenzyl)oxy)carbonyl)-L-threonine (95 mg, 0.23 mmol) in DCM (2 mL) was added HATU (86 mg, 0.23 mmol) and DIPEA (131 mg, 1.02 mmol) and the mixture stirred at room temperature for 30 min. 2-(piperidin-4-yl)thiazole (50 mg, 0.29 mmol) was added and stirring continued for another 2 h. The reaction was diluted with water (10 mL) and extracted with DCM (30 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue obtained was purified by prep-TLC (eluent: DCM : MeOH = 15 : 1) and prep-HPLC to afford 4-nitrobenzyl ((2S,3R)-3-((2- oxabicyclo[2.2.2]octan-4-yl)methoxy)-1-oxo-1-(4-(thiazol-2-yl) piperidin-1-yl) butan-2-yl) carbamate (95 mg, 72%) as a white solid. LCMS m / z = 573.0 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.21 (dd, J = 20.3, 8.1 Hz, 2H), 7.72 (s, 1H), 7.67 – 7.37 (m, 4H), 5.18 (s, 2H), 4.45 (d, J = 35.5 Hz, 2H), 4.15 (d, J = 29.4 Hz, 1H), 3.65 – 3.41 (m, 4H), 3.15 (d, J = 9.2 Hz, 1H), 2.98 (d, J = 9.1 Hz, 1H), 2.86 – 2.73 (m, 1H), 2.15 – 1.94 (m, 2H), 1.85 – 1.64 (m, 2H), 1.50 (s, 6H), 1.41 – 1.30 (m, 2H), 1.24 (s, 2H), 1.04 (s, 3H).

[0328] Step 3: (2S,3R)-3-((2-oxabicyclo[2.2.2]octan-4-yl)methoxy)-2-amino-1-(4-(thiazol-2- yl)piperidin-1-yl)butan-1-one: To a solution of 4-nitrobenzyl ((2S,3R)-3-((2- oxabicyclo[2.2.2]octan-4-yl) methoxy)-1-oxo-1-(4-(thiazol-2-yl) piperidin-1-yl) butan-2-yl) carbamate (95 mg, 0.17 mmol) in MeOH (2 mL) was added 10% Pd / C (38 mg). The reaction was heated at 50 °C under a H2atmosphere for 2 h. The catalyst was removed by filtration through celite and the filtrate concentrated to afford (2S,3R)-3-((2-oxabicyclo[2.2.2]octan-4-yl)methoxy)-2-amino-1-(4-(thiazol-2-yl)piperidin-1-yl)butan-1-one (61 mg, 94%) which was used directly in the next step. LCMS m / z = 394.3 [M+H]+.

[0329] Synthesis of 2-(piperidin-4-yl)thiazole

[0330] Step 1: tert-butyl 4-(thiazol-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate: To a solution of 2-bromothiazole (1.0 g, 6.1 mmol) in a mixture of 1,4-dioxane (10 mL) and water (2.5 mL) was added tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine- 1(2H)-carboxylate (2.0 g, 6.7 mmol), Na2CO3(1.9 g, 18.3 mmol) and Pd(dppf)Cl2(446 mg, 0.61 mol). The reaction was heated at 90 °C under a N2atmosphere overnight then was diluted with water (50 mL) and extracted with EtOAc (100 mL × 2). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue obtained was purified by column chromatography on silica gel (eluent: Pet. Ether / EtOAc = 10 / 1, v / v) to afford tert-butyl 4- (thiazol-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.0 g, 63%) as a yellow oil. LCMS m / z = 267.1 [M+H]+;1H NMR (400 MHz, Chloroform-d) δ 7.75 (d, J = 3.2 Hz, 1H), 7.22 (d, J = 3.3 Hz, 1H), 6.56 (s, 1H), 4.16 – 4.07 (m, 2H), 3.64 (t, J = 5.8 Hz, 2H), 2.70 (s, 2H), 1.48 (s, 9H).

[0331] Step 2: tert-butyl 4-(thiazol-2-yl)piperidine-1-carboxylate: To a solution of tert-butyl 4-(thiazol-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (430 mg, 1.61 mmol) in MeOH (3 mL) was added 10% Pd / C (215 mg). The reaction was stirred under H2atmosphere overnight. The catalyst was removed by filtration through celite and the filtrate concentrated to afford tert-butyl 4-(thiazol-2-yl)piperidine-1-carboxylate (380 mg crude, 88%) as a yellow oil, which was used without purification. LCMS m / z = 291.2 [M + Na]+.

[0332] Step 3: 2-(piperidin-4-yl)thiazole: To a solution of tert-butyl 4-(thiazol-2-yl)piperidine- 1-carboxylate (80 mg, 0.30 mmol) in DCM (1 mL) was added a solution of HCl in dioxane (1M, 1 mL). The reaction was stirred at room temperature for 2 h then the solvent was removed under reduced pressure to afford 2-(piperidin-4-yl)thiazole (50 mg, 100%) as a yellow oil, which was used without purification. LCMS m / z = 169.2 [M+H]+.

[0333] Synthesis of (S)-N-((2S,3R)-3-(2-oxabicyclo[2.2.2]octan-4-ylmethoxy)-1-oxo-1-(4- (thiazol-2-yl)piperidin-1-yl)butan-2-yl)-6-(1-benzyl-1H-pyrazole-4-carbonyl)-2-(1- (trifluoromethyl)cyclopropanecarbonyl)-2,6-diazaspiro[3.4]octane-8-carboxamide (I-69):

[0334] Synthesis of Methyl trityl-L-threoninate: To a solution of methyl L-threoninate hydrochloride (1.00 g, 5.9 mmol) and triethylamine (1.2 g, 11.8 mmol) in chloroform (20 mL) at 0°C was added TrtCl (1.64 g, 5.9 mmol). The resulting mixture was stirred at 0°C for 12 hours. The reaction mixture was then diluted with water (30 ml) and extracted with ethyl acetate (10 ml x3). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude residue which was purified by silica gel chromatography using a 2% ethyl acetate in hexane gradient to afford methyl trityl-L-threoninate (1.4 g, 63% yield) as a colorless oil.1HNMR (400 MHz, DMSO-d6): δ 7.43 (d, J = 7.2 Hz, 6H), 7.27 (t, J = 8.0 Hz, 6H), 7.21-7.17 (m, 3H), 5.01 (d, J = 4.7 Hz, 1H), 3.90-3.97 (m, 1H), 3.22-3.18 (m, 1H), 3.03 (s, 3H), 2.69 (d, J = 10.0 Hz, 1H), 1.09 (d, J = 6.4 Hz, 3H).

[0335] Synthesis of Methyl (2S,3S)-3-methyl-1-tritylaziridine-2-carboxylate: To a stirred solution of methyl trityl-L-threoninate (10.0 g, 26.6 mmol) in pyridine (30 mL) at 0°C was added a solution of 4-toluenesulfonyl chloride (15.2 g, 79.9 mmol) in pyridine (40 ml). The resulting mixture was stirred at 0°C for 20 hours, then raised to 50°C and stirred for 12 hours. The reaction mixture was concentrated to remove the solvent. The residue was diluted with water (300 ml) and extracted with ethyl acetate (100 ml x3). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude residue which was purified by silica gel chromatography using a 0-2% ethyl acetate in hexane gradient to afford methyl (2S,3S)-3-methyl-1-tritylaziridine-2-carboxylate (6.300 g, 67% yield) as a light yellow oil.1HNMR (400 MHz, DMSO-d6): δ 7.42-7.44 (m, 6H), 7.31-7.34 (m, 6H), 7.27- 7.24 (m, 3H), 3.67 (s, 3H), 1.72 (d, J = 6.4 Hz, 1H), 1.59-1.54 (m, 1H), 1.29 (d, J = 5.2 Hz, 3H).

[0336] Synthesis of 1-Benzyl 2-methyl (2S,3S)-3-methylaziridine-1,2-dicarboxylate : To a stirred solution of methyl (2S,3S)-3-methyl-1-tritylaziridine-2-carboxylate (5.2 g, 14.7 mmol) in a mixture of methanol (10 mL) and dichloromethane (10 ml) at 0°C was added 2,2,2-trifluoroacetic acid (11.6 ml, 14.7 mmol). The resulting mixture was stirred at 0°C for 10 minutes and then concentrated to remove the solvent. The residue was diluted with diethyl ether (30 ml) and extracted with water (20 ml x3). The combined aqueous layer was basified to pH 9 with aqueous sodium bicarbonate solution at 0°C. Ethyl acetate (50 ml) was added to the aqueous solution, followed by addition of benzyl chloroformate (2.5 g, 14.7 mmol) at 0°C. The resulting mixture was stirred at 0°C for 20 minutes. TLC showed the reaction was complete. The resulting mixture was extracted with ethyl acetate (20 ml x3). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude residue which was purified by silica gel flash chromatography using a 20% ethyl acetate in hexane gradient to afford 1-benzyl 2-methyl (2S,3S)-3-methylaziridine-1,2-dicarboxylate (3.2 g, 89% yield) as a colorless oil.1HNMR (400 MHz, DMSO-d6): δ 7.43-7.29 (m, 5H), 5.09 (s, 2H), 3.69 (s, 3H), 3.37 (d, J = 6.8 Hz, 1H), 3.00-2.95 (m, 1H), 1.18 (d, J = 6.4 Hz, 3H). MS: [MH]+250.1.

[0337] Synthesis of (2S,3R)-methyl 3-(2-oxabicyclo[2.2.2]octan-4-ylmethoxy)-2- (((benzyloxy)carbonyl)amino)butanoate: To a solution of 2-oxabicyclo[2.2.2]octan-4- ylmethanol (0.300 g, 2.110 mmol) and (2S,3S)-1-benzyl 2-methyl 3-methylaziridine-1,2- dicarboxylate (0.526 g, 2.110 mmol) in CHCl3(5 mL) at 0°C was added boron trifluoride-diethyl ether complex (0.060 g, 0.422 mmol) slowly, and the resulting mixture was stirred at 0-5°C under nitrogen atmosphere for 1 hour. The reaction mixture was concentrated to give a crude residue which was purified by silica gel flash column chromatography using a hexane-ethyl acetate- dichloromethane (7:1:1 v / v / v) gradient then a hexane-ethyl acetate-dichloromethane (3:1:1 v / v / v) gradient to afford (2S,3R)-methyl 3-(2-oxabicyclo[2.2.2]octan-4-ylmethoxy)-2- (((benzyloxy)carbonyl)amino)butanoate (0150 g, 18%) as a colorless oil. MS: [MH]+392.20.

[0338] Synthesis of (2S,3R)-3-(2-oxabicyclo[2.2.2]octan-4-ylmethoxy)-2- (((benzyloxy)carbonyl)amino)butanoic acid: To a solution of (2S,3R)-methyl 3-(2- oxabicyclo[2.2.2]octan-4-ylmethoxy)-2-(((benzyloxy)carbonyl)amino)butanoate (0.660 g, 1.686 mmol) in tetrahydrofuran (8 mL)-methanol (4 mL)-water (2 mL) was added lithium hydroxide monohydrate (0.142 g, 3.372 mmol); the resulting mixture was stirred at room temperature for 3hours, and then concentrated. The residue was diluted with water (10 mL) and extracted with ether (10 mL). The aqueous layer was acidified to pH 3-4 with hydrochloric acid (2.0 N), and extracted with dichloromethane (15 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give (2S,3R)-3-(2-oxabicyclo[2.2.2]octan-4-ylmethoxy)-2- (((benzyloxy)carbonyl)amino)butanoic acid (0.550 g, yield 86%) as a colorless oil which was used in the next step without further purification. MS: [MH]+378.20

[0339] Synthesis of Benzyl ((2S,3R)-3-(2-oxabicyclo[2.2.2]octan-4-ylmethoxy)-1-oxo-1-(4- (thiazol-2-yl)piperidin-1-yl)butan-2-yl)carbamate: To a solution of (2S,3R)-3-(2- oxabicyclo[2.2.2]octan-4-ylmethoxy)-2-(((benzyloxy)carbonyl)amino)butanoic acid (0.570 g, 1.510 mmol), 2-(piperidin-4-yl)thiazole (0.280 g, 1.661 mmol), and N-ethyl-N-isopropylpropan- 2-amine (0.585 g, 4.530 mmol) in N,N-dimethylformamide (11 mL) at 0-5°C was added (2-(7- Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (HATU, 0.689 g, 1.812 mmol). The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (10 mL). The organic phase was washed with water (10 mL × 3) and brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude residue which was purified by silica gel flash column chromatography using a 10% ethyl acetate / hexane gradient to afford benzyl ((2S,3R)-3-(2-oxabicyclo[2.2.2]octan-4-ylmethoxy)-1-oxo-1-(4-(thiazol-2-yl)piperidin-1- yl)butan-2-yl)carbamate (0.680 g, 80% yeild) as a colorless oil. MS: [MH]+528.60.

[0340] Synthesis of (2S,3R)-3-(2-oxabicyclo[2.2.2]octan-4-ylmethoxy)-2-amino-1-(4- (thiazol-2-yl)piperidin-1-yl)butan-1-one TFA salt: A solution of benzyl ((2S,3R)-3-(2- oxabicyclo[2.2.2]octan-4-ylmethoxy)-1-oxo-1-(4-(thiazol-2-yl)piperidin-1-yl)butan-2- yl)carbamate (0.600 g, 1.136 mmol) in trifluoroacetic acid (6 mL) was stirred at 40°C overnight. The reaction mixture was concentrated to give (2S,3R)-3-(2-oxabicyclo[2.2.2]octan-4- ylmethoxy)-2-amino-1-(4-(thiazol-2-yl)piperidin-1-yl)butan-1-one TFA salt (575 mg, 100% yield) as a yellow oil which was used in the next step without further purification. MS: [MH]+395.10.

[0341] Synthesis of 2,5-Dioxopyrrolidin-1-yl 1-(trifluoromethyl)cyclopropane-1- carboxylate: A mixture of 1-(trifluoromethyl)cyclopropane-1-carboxylic acid (20.000 g, 129.87mmol), 1-hydroxypyrrolidine-2,5-dione (14.930 g, 129.87 mmol), and EDCI (30.000 g, 156.25 mmol) in dichloromethane (100 mL) was stirred at room temperature under nitrogen atomsphere overnight. The reaction mixture was concentrated to give a crude residue which was purified by silica gel column chromatography using a dichloromethane gradient to afford 2,5-dioxopyrrolidin- 1-yl 1-(trifluoromethyl)cyclopropane-1-carboxylate (29.500 g, yield 90%) as a white solid.1HNMR (400 MHz, CDCl3): δ 2.83 (s, 4H), 1.78-1.75 (m, 2H), 1.61-1.58 (m, 2H).

[0342] Synthesis of 2,5-Dioxopyrrolidin-1-yl 1-benzyl-1H-pyrazole-4-carboxylate: A mixture of 1-benzyl-1H-pyrazole-4-carboxylic acid (10.000 g, 49.50 mmol), 1-hydroxypyrrolidine-2,5- dione (14.930 g, 129.87 mmol), and EDCI (9.500 g, 49.50 mmol) in dichloromethane (70 mL) was stirred at room temperature under nitrogen atomsphere overnight. The reaction mixture was concentrated to give a crude residue which was purified by silica gel flash column chromatography using a dichloromethane gradient to afford 2,5-dioxopyrrolidin-1-yl 1-benzyl-1H-pyrazole-4- carboxylate (11.840 g, yield 80%) as a white solid. MS: [MH]+300.20.

[0343] Synthesis of (S)-6-benzyl-2,6-diazaspiro[3.4]octane-8-carboxylic acid hydrochloride: To a mixture of (S)-6-ben...

Claims

CLAIMS We claim:

1. A compound of Formula IA:or a pharmaceutically acceptable salt thereof, wherein: RAisRBis hydrogen, an optionally substituted C1-6aliphatic group, -OR, -NR2or a halogen; L1is a covalent bond or a saturated or unsaturated, straight or branched, optionally substituted bivalent C1-6hydrocarbon chain, wherein 0-2 methylene units of L1are independently replaced by -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -C(S)-, -NRS(O)2-, - S(O)2NR-, -NRC(O)-, -C(O)NR-, -OC(O)NR-, -NRC(O)O-, or -NRC(O)NR-; R1is hydrogen, an optionally substituted C1-6aliphatic group, or an optionally substituted cyclic group selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring that is optionally bridged bicyclic or spirocyclic (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and an 8-10 membered bicyclic heteroaromatic ring (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur);R2is hydrogen, an optionally substituted C1-6aliphatic group, –C1-6alkylene-OR,–C1-3alkylene-O-C1-3alkylene-R,–C(O)OR, –C(O)NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -P(O)R2, – C(O)NRS(O)2R, or an optionally substituted cyclic group selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and an 8-10 membered bicyclic heteroaromatic ring (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur); and R3is hydrogen; or R2and R3together with the intervening carbon atom form an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring, or an optionally substituted 3-7 membered saturated or partially unsaturated heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur); R4is an optionally substituted cyclic group selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and an 8-10 membered bicyclic heteroaromatic ring (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur); and R5is hydrogen; or R4and R5together with the intervening nitrogen atom form an optionally substituted 4-7 membered saturated, or partially unsaturated heterocyclic ring (having 0-2 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur), or anoptionally substituted heteroaryl ring (having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur); L2is a saturated or unsaturated, straight or branched, optionally substituted bivalent C1-4hydrocarbon chain, wherein 0-2 methylene units of L2are independently replaced by -O-, -NR-, - S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -C(S)-, -NRS(O)2-, -S(O)2NR-, -NRC(O)-, - C(O)NR-, -OC(O)NR-, -NRC(O)O-, or -NRC(O)NR-; R6is an optionally substituted C1-6aliphatic group, or a cyclic group selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and an 8-10 membered bicyclic heteroaromatic ring (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the cyclic group is optionally substituted with one or more instances of R7; each instance of R7is independently halogen, –CN, –NO2, –OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, –C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, –N(R)S(O)2R, an optionally substituted C1-6aliphatic group, an optionally substituted C1-6aliphatic-Cy group, or Cy; L3is a saturated or unsaturated, straight or branched, optionally substituted bivalent C1-4hydrocarbon chain, wherein 0-2 methylene units of L3are independently replaced by -O-, -NR-, - S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -C(S)-, -NRS(O)2-, -S(O)2NR-, -NRC(O)-, - C(O)NR-, -OC(O)NR-, -NRC(O)O-, or -NRC(O)NR-; R8is a cyclic group selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatomsindependently selected from nitrogen, oxygen, and sulfur), a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and an 8-10 membered bicyclic heteroaromatic ring (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the cyclic group is optionally substituted with one or more instances of R9; each instance of R9is independently halogen, –CN, –NO2, –OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, –C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, –N(R)S(O)2R, an optionally substituted C1-6aliphatic group, an optionally substituted C1-6aliphatic-Cy group, or Cy; each Cy is independently an optionally substituted cyclic group selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and a 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); and each R is independently hydrogen, or an optionally substituted C1-6aliphatic group, an optionally substituted phenyl, an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring, an optionally substituted 3-7 membered saturated or partially unsaturated heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), or an optionally substituted 5-6 membered heteroaryl ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); or when there are two R groups on the same nitrogen they are taken together with their intervening atoms to form a cyclic group selected from a 4-7 membered saturated, partially unsaturated, or heteroaryl ring (having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur), and a 7-12 membered saturated orpartially unsaturated bicyclic heterocyclic ring that is optionally bridged bicyclic or spirocyclic (having 1-4 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur) wherein the cyclic group is optionally substituted with one or more instances of R9; wherein the compound is notor a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, wherein the compound is of Formula Ior a pharmaceutically acceptable salt thereof, wherein: RAisL1is a covalent bond or a saturated or unsaturated, straight or branched, optionally substituted bivalent C1-6hydrocarbon chain, wherein 0-2 methylene units of L1are independently replaced by -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -C(S)-, -NRS(O)2-, - S(O)2NR-, -NRC(O)-, -C(O)NR-, -OC(O)NR-, -NRC(O)O-, or -NRC(O)NR-; R1is hydrogen, an optionally substituted C1-6aliphatic group, or an optionally substituted cyclic group selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring,phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring that is optionally bridged bicyclic or spirocyclic (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and an 8-10 membered bicyclic heteroaromatic ring (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur); R2is an optionally substituted C1-6aliphatic group, –C1-6alkylene-OR, –C(O)OR, – C(O)NR2, –C(O)NRS(O)2R, or an optionally substituted cyclic group selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and a 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); R3is hydrogen; R4and R5together with the intervening nitrogen atom form an optionally substituted 4-7 membered saturated, or partially unsaturated heterocyclic ring (having 0-2 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur), or an optionally substituted heteroaryl ring (having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur); L2is a saturated or unsaturated, straight or branched, optionally substituted bivalent C1-4hydrocarbon chain, wherein 0-2 methylene units of L2are independently replaced by -O-, -NR-, - S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -C(S)-, -NRS(O)2-, -S(O)2NR-, -NRC(O)-, - C(O)NR-, -OC(O)NR-, -NRC(O)O-, or -NRC(O)NR-; R6is an optionally substituted C1-6aliphatic group, or a cyclic group selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, andsulfur), a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and an 8-10 membered bicyclic heteroaromatic ring (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the cyclic group is optionally substituted with one or more instances of R7; each instance of R7is independently halogen, –CN, –NO2, –OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, –C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, –N(R)S(O)2R, an optionally substituted C1-6aliphatic group, an optionally substituted C1-6aliphatic-Cy group, or Cy; L3is a saturated or unsaturated, straight or branched, optionally substituted bivalent C1-4hydrocarbon chain, wherein 0-2 methylene units of L3are independently replaced by -O-, -NR-, - S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -C(S)-, -NRS(O)2-, -S(O)2NR-, -NRC(O)-, - C(O)NR-, -OC(O)NR-, -NRC(O)O-, or -NRC(O)NR-; R8is a cyclic group selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and an 8-10 membered bicyclic heteroaromatic ring (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the cyclic group is optionally substituted with one or more instances of R9; each instance of R9is independently halogen, –CN, –NO2, –OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, –C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2,-N(R)S(O)2NR2, –N(R)S(O)2R, an optionally substituted C1-6aliphatic group, an optionally substituted C1-6aliphatic-Cy group, or Cy; each Cy is independently an optionally substituted cyclic group selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and a 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); and each R is independently hydrogen, or an optionally substituted C1-6aliphatic group, an optionally substituted phenyl, an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring, an optionally substituted 3-7 membered saturated or partially unsaturated heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), or an optionally substituted 5-6 membered heteroaryl ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); or when there are two R groups on the same nitrogen they are taken together with their intervening atoms to form a cyclic group selected from a 4-7 membered saturated, partially unsaturated, or heteroaryl ring (having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur), and a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring that is optionally bridged bicyclic or spirocyclic (having 1-4 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur) wherein the cyclic group is optionally substituted with one or more instances of R9. .

3. The compound of claim 1 or 2, wherein RAisor a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 or 2, wherein RAisor a pharmaceutically acceptable salt thereof.

5. The compound of claim 1, 2, or 4, or a pharmaceutically acceptable salt thereof, wherein R4and R5together with their intervening nitrogen atom form an optionally substituted 4-7 membered saturated, or partially unsaturated heterocyclic ring (having 0-2 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur).

6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein RAis a substituent of Table B.

7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein RBis H.

8. The compound of any one of claims 1-3, 6, and 7, or a pharmaceutically acceptable salt thereof, wherein L1isor9. The compound of any one of claims 1-3 and 6-8, or a pharmaceutically acceptable salt thereof, wherein L1is, wherein theon the left ofis attached to R1.

10. The compound of any one of claims 1-3 and 6-9, or a pharmaceutically acceptable salt thereof, wherein R1is11. The compound of any one of claims 1-3 and 6-10, or a pharmaceutically acceptable salt thereof, wherein R1is12. The compound of any one of claims 1-3 and 6-11, or a pharmaceutically acceptable salt thereof, wherein R2is an optionally substituted C1-6aliphatic group, –C1-6alkylene-OR,– C(O)OR, –C(O)NR2, –C(O)NRS(O)2R, or an optionally substituted phenyl; and R3is hydrogen.

13. The compound of any one of claims 1-3 and 6-12, or a pharmaceutically acceptable salt thereof, wherein R2is –C(O)NR2, wherein the two R groups, of –C(O)NR2, taken together with the intervening nitrogen atom, form a cyclic group selected from a 4-7 membered saturated heterocyclic ring (having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur), and a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring that is optionally bridged bicyclic or spirocyclic (having 1-4 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur) wherein the cyclic group is optionally substituted with one or more instances of R9; wherein R9is selected from –CN, -C(O)O(C1-3alkyl), –O(C1-3alkyl), C1-3haloalkyl, halo, optionally substituted C1-6aliphatic group, an optionally substituted cyclic group selected phenyl, a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and a 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); and R3is hydrogen.

14. The compound of any one of claims 1-3 and 6-13, or a pharmaceutically acceptable salt thereof, wherein R2is a substituent of Table A.

15. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt thereof, wherein L2is16. The compound of any one of claims 1-15, or a pharmaceutically acceptable salt thereof, wherein R6is17. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt thereof, wherein -L2-R6is a substituent of Table C.

18. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt thereof, wherein L3is19. The compound of any one of claims 1-15, or a pharmaceutically acceptable salt thereof, wherein R8is:wherein R9is -CF3, -CN, -C(O)OH, -C(O)OCH3, -C(O)OCH2CH3, -C(O)OC(CH3)3, or - C(O)OCH2CH2CH3; R8iswherein R9is methyl; or R8is20. The compound of any one of claims 1-19, or a pharmaceutically acceptable salt thereof, wherein -L3-R8is a substituent of Table D.

21. The compound of any one of claims 1-20, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula IA is a compound of Formula IIA:

22. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula IA is a compound of Formula IIB:

23. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula IA is a compound of Formula II:

24. The compound of any one of claims 1-3 and 6-23, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula IA is a compound of Formula IIIa:wherein: L1isR2is –C(O)NR2, wherein the two R groups of –C(O)NR2, taken together with the intervening nitrogen atom, form a cyclic group selected from an optionally substituted 4-7 membered saturated ring (having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur), and a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring that is optionally bridged bicyclic or spirocyclic (having 1- 4 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur) wherein the cyclic group is optionally substituted with one or more instances of R9; wherein R9is selected from –CN, -C(O)O(C1-3alkyl), –O(C1-3alkyl), C1-3haloalkyl, halo, optionally substituted C1-6aliphatic group, an optionally substituted cyclic group selected from phenyl, a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and a 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); and R3is hydrogen.

25. The compound of any one of claims 1, 2, 4-7, and, 15-23 or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I or IA is a compound of Formula IIIb:wherein: R4and R5together with the intervening nitrogen atom form an optionally substituted 4-7 membered saturated, or partially unsaturated heterocyclic ring (having 0-2 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur).

26. The compound of any one of claims 1-25, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula IA is a compound of Formula IVa:

27. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I or IA is a compound of Formula IVb:

28. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I or IA is a compound of Formula IVc:

29. The compound of any one of claims 1-28, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I or IA is a compound of Formula Va:

30. The compound of any one of claims 1-29, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I or IA is a compound of Formula Vb:

31. The compound of any one of claims 1-3, 6-24, and 26-30, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I or IA is a compound of Formula VIa:wherein: L1isR2is –C(O)NR2, wherein the two R groups, of –C(O)NR2, taken together with the intervening nitrogen atom, form a cyclic group selected from a 4-7 membered saturated heterocyclic ring (having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur), and a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring that is optionally bridged bicyclic or spirocyclic (having 1-4 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur) wherein the cyclic group is optionally substituted with one or more instances of R9; wherein R9is selected from –CN, -C(O)O(C1-3alkyl), –O(C1-3alkyl), C1-3haloalkyl, halo, optionally substituted C1-6aliphatic group, an optionally substituted cyclic group selected phenyl, a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and a 5-6 memberedmonocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); and R3is hydrogen. .

32. The compound of any one of claims 1-3, 6-24, 26, 27, and 29-31, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I or IA is a compound of Formula VIb:

33. The compound of any one of claims 1-3, 6-24, 26, 28, and 29-31, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I or IA is a compound of Formula VIc:

34. The compound of any one of claims 1, 2, 4-7, 15-23, and 25-30, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I or IA is a compound of Formula VId:wherein R4and R5together with the intervening nitrogen atom form an optionally substituted 4-7 membered saturated, or partially unsaturated heterocyclic ring (having 0-2 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur).

35. The compound of any one of claims 1, 2, 4-7, 15-23, 25-27, 29, 30, and 34, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I or IA is a compound of Formula VIe:

36. The compound of any one of claims 1, 2, 4-7, 15-23, 25, 26, 28-30, 34, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I or IA is a compound of Formula VIf:

37. The compound of any one of claims 1-3, 6-24, and 26-33, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I or IA is a compound of Formula VIIa:VIIa wherein: R1is phenyl,or -CF3; L1is andthe two R groups on the same nitrogen are taken together with their intervening atoms to form a cyclic group selected from a 4-7 membered saturated, partially unsaturated, or heteroaryl ring (having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur), and a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring that is optionally bridged bicyclic or spirocyclic (having 1-4 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur) wherein the cyclic group is optionally substituted with one or more instances of R9.

38. The compound of any one of claims 1-3, 6-24, 26, 27, 29-33, and 37 or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I or IA is a compound of Formula VIIb:

39. The compound of any one of claims 1-3, 6-24, 26, 28-31, 33, and 37, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I or IA is a compound of Formula VIIc:

40. The compound of any one of claims 1-3 and 6-24, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I or IA is a compound of Formula VIIIa, VIIIb, or VIIIc:wherein Z is a cyclic group taken together with its attached nitrogen to form a cyclic group selected from a 4-7 membered saturated, partially unsaturated, or heteroaryl ring (having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur), and a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring that is optionally bridged bicyclic or spirocyclic (having 1-4 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur) wherein the cyclic group is optionally substituted with one or more instances of R9.

41. The compound of any one of claims 1-3 and 6-24, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I or IA is a compound of Formula IXa, IXa*, IXa**, IXb, IXb*, IXb**, IXc, IXc*, or IXc**:wherein Z is a cyclic group taken together with its attached nitrogen to form a cyclic group selected from a 4-7 membered saturated, partially unsaturated, or heteroaryl ring (having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur), and a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring that is optionally bridged bicyclic or spirocyclic (having 1-4 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur) wherein the cyclic group is optionally substituted with one or more instances of R9.

42. The compound of any one of claims 1-3 and 6-24, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I or IA is a compound of Formula XIIa or XIIb:whereinis -CH2-Cy or an optionally substituted cyclic group selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 5-6 memberedmonocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and an 8-10 membered bicyclic heteroaromatic ring (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur).

43. The compound of any one of claims 1-3, 6-24, and 42, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I or IA is a compound of Formula XIIIa, XIIIb, XIIIc, or XIIId:wherein R10has from 0 to 3 instances each independently selected from halogen, –CN, – NO2, –OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, – C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, - N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, –N(R)S(O)2R, an optionally substituted C1-6aliphatic group, an optionally substituted C1-6aliphatic-Cy group, and Cy.

44. The compound of any one of claims 1-3 and 6-24, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I or IA is a compound of Formula XIV:wherein R11is hydrogen, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, – C(O)NR2, -C(O)N(R)OR, an optionally substituted C1-6aliphatic group, an optionally substituted C1-6aliphatic-Cy group, or Cy.

45. A compound of Table 1, or a pharmaceutically acceptable salt thereof.

46. A pharmaceutically acceptable composition comprising a compound of any of claims 1- 45, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient, vehicle, adjuvant or diluent.

47. The pharmaceutically acceptable composition of claim 46, further comprising an additional therapeutic agent.

48. A method of inhibiting the activity of a cyclin-dependent kinase (CDK) comprising contacting a compound of any one of claims 1-45 with the CDK.

49. A method of treating a disease or disorder associated with CDK2 activity in a patient comprising administering to the patient in need thereof a compound of any one of claims 1-45 or a pharmaceutical composition of claim 46 or 47.

50. The method of claim 49, wherein the disease or disorder associated with CDK2 activity is selected from cancers, myeloproliferative disorders, autoimmune disorders, inflammatory disorders, viral infections, and fibrotic disorders.51 . The method of claim 50, wherein the disease or disorder associated with CDK2 activity is a cancer.

52. The method of claim 50, wherein the disease or disorder associated with CDK2 activity is a cancer selected from breast cancer, ovarian cancer, bladder cancer, uterine cancer, prostate cancer, lung cancer, esophageal cancer, head and neck cancer, colorectal cancer, kidney cancer, liver cancer, pancreatic cancer, stomach cancer, melanoma and thyroid cancer.

53. The method of claim 50, wherein the disease or disorder associated with CDK2 activity is liver fibrosis.

54. The method of claim 50, wherein the disease or disorder associated with CDK2 activity is Cushing’s disease.

55. The method of claim 50, wherein the disease or disorder associated with CDK2 activity is polycystic kidney disease.

56. The method of claim 50, wherein the disease or disorder associated with CDK2 activity is Alzheimer’s disease.

57. A method of reducing male fertility comprising administering to the patient in need thereof a compound of any one of claims 1-45 or a pharmaceutical composition of claim 46 or 47.

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